Beta Amyloid Peptide

The secret of Eta Black by Ananya Sharma

amyloidorg@gmail.com (Unknown) — Fri, 30 Dec 2022 17:15:00 -0800

The secret of Eta Black by Ananya Sharma

A man sitting behind the bars named Eta black has no clue what is happening with him. He was searching for questions like, why he has been put inside jail? Why everyone is hating him? Why everyone is abusing him with non- patriotic slogans. He was taken by Hercules Soldiers.

Eta black was born in Orion constellation and his parents left him in front of an orphanage where he grew with his friend Canopus, Rigel and Polaris , though Rigal was his best friend. On a fine day all five friends went for walk in the forest. Unfortunately there came a leopard and they ran away in different directions to save themselves and got separated but Regal and Eta black were together fall down and got fainted.

Rigal was picked up by a family who donot have children and has been taken to the Hercules constellation. Rigal inquired about his friend Eta black and they informed that he has been taken by King’s Soldiers and would be hanged the next day.

Rigal got worried and started thinking how to save his friend and start seeking guidance from the family to give him some clue how he can save his friend.

Mr. Vega, the head of the family offered wine amphora along with roasted sorghum to Rigal and started thinking along Rigal for the solution for the saving Eta black life.

While thinking, Mr, Vega said, I know how to come out from Jail, but I donot know how to go inside the jai?

Rigal asked with surprise, what do you mean by that?

Vega said, I mean my ancestors had made this Palace and my grandfather was a great architect, he was put inside the jail after finishing this beautiful king’s palace since the king don’t want him to make similar palace for any other king. Hence my grandfather, know that so he had made a tunnel from the palace to the sea. He used that tunnel and came out and settle in the other constellation.

But that was palace this is jail, asked Rigal?

Now that palace has been converted into Jail, answered Mr. Vega

While Rigal was thinking and they heard a noise outside, both came out and saw that the Kings ride was passing from their street. Rigal started walking aggressively and hit on a Kings Solder on his face saying that “O kings Solder, am your father and hit the face with aggressive slap” The Soldier came and started hitting him to almost death, Vega tried to save him but all vain. The king ordered the soldiers to put both of them in the jail as he was getting late for Dawat

In the jail, whatever they have left with energy, they started looking for Eta black and could not found him, then they started shouting with a different type of voice which only Eta black can understand.

When Eta black heard the voice, he woke up from his unconsciousness and started walking towards Rigal. Both friends met and started crying like anything and now everyone start abusing both friends with non-patriotic slogans.

Rigal asked why they are abusing us, Eta said, I am also looking the answer of this question?

At the same time, Mr. Vega came towards them and asked not to make any noise we will leave this jail tonight.

But Eta said, that I will not leave this jail until I get the answers, why they are abusing us without any reasons.

Vega and Rigal try to convince Eta but all in vain and hence they thought how to get answers of Eta’s question.

Vega suggested let’s talk to the prisoners, who is abusing to understand the reasons, but the moment they went to ask the prisoners, the prisoners started beating them. Now they have no energy left and fall sleep.

Eta dreamed that he is being hanged by the Kings Soldiers and woke up suddenly in the night. He was very frightened and cried, at the same time both Vega and Rigal also woke up by hearing his voice. Finally they decided to go out through the tunnel and later they will find the answers for Eta’s questions.

Suddenly they realize that the door of their barrack has been locked from outside. Regal said that I can open the door if I got a small pin since I know how to open locks. Trio started looking for Pin but could not found inside the barrack. Vega saw a wood stick and picked up the wood stick, sharpen with his teeth and handed over to Regal for opening the lock.

After multiple efforts, they were finally able to open the lock, they came out with stifled steps and started crossing the corridor. Now it is Mr. Vega turn to lead them and take them out from Jail. He said lets us look for a “Ficus bengalensis” tree but it was extremely dark night, they were worried for any noise.

Suddenly the king came back from Dawat and asked the Soldiers to bring them in the court to be hanged in the night itself.

The Soldiers ran towards the jail barrack and to their surprise, they could not found them inside that, all these is being observed by Eta black, Regal and Vega. The solders whispered themselves lets search them otherwise King will kill us. To search them they turn on the lights inside and outside the Jail. THe moment light turns ups, Eta saw the Ficus bengalensis tree and they started running towards the tree, while running, Vega saw another Ficus bengalensis tree, he stopped them and said, lets us take pause and decided which one is right tree. By this time, they have noticed by the King Soldiers and they started celebrating saying that, ohoo hurray they are inside the Jail and become slow. Eta Black got an intuition and said the old one would be the right tree and they started running with full energy toward the old tree. The Soldier were still in dilemma that where they will go they will remain inside the Jail, so they decided not to chase them since they thought that when they will get tired they, we will catch them.

Trio went near the Ficus bengalensis tree and Vega started looking for clue, they found a bunch of large stones and started putting them away. The Solider thought that they are making an arrangement for sleeping. They have lifted all the stones but one and could not found any clue for exit, but the moment Eta black take out the last stone, the saw lot of water through the bark, everyone without wasting time jumped in the water and started swimming in the dark night and reached the sour and boundary of the kingdom.

To be continued

Short story by Ananya Sharma Jind Haryana

Beta Amyloid Peptide: Research Paper : SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature

amyloidorg@gmail.com (Unknown) — Mon, 29 Mar 2021 21:20:00 -0700

SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature

Abstract

Introduction: Accumulating evidence shows that SQSTM1 plays a vital role in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which represent a neurodegenerative disease continuum. Here, we report a novel SQSTM1 variant in a patient presenting with progressive nonfluent aphasia (PNFA) and progressive bulbar palsy (PBP). Relevant literature about FTD and FTD-ALS caused by SQSTM1 mutation was reviewed to better understand its clinical features.

Methods: We collected data from a 66-year-old male patient with a novel heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene who was diagnosed with PNFA and PBP and performed a PubMed literature search using the advanced research criteria: [("frontotemporal lobar degeneration") OR ("frontotemporal dementia") OR ("amyotrophic lateral sclerosis") OR ("motor neuron disease")] AND ("SQSTM1"). The clinical features of FTD and FTD-ALS related to SQSTM1 mutation were summarized based on previous cases and our new case.

Results: The initial symptom of the current patient was progressive verb finding difficulties and effortful speech output, which developed into dysarthria and dysphagia in subsequent months. The results, including tongue atrophy, fasciculations, neurogenic changes, and mild left dominant hypometabolism of 18F-fluorodeoxyglucose PET in the frontal cortex, suggest the possibility of PNFA and PBP. A novel likely pathogenic heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene was identified. The literature search revealed a total of 33 FTD and FTD-ALS cases related to the SQSTM1 mutation with detailed clinical information. The mean age of onset (including our patient) was 63.5 ± 9.7 years. bvFTD was the most common clinical phenotype. The missense mutation in the SQSTM1 gene coding region and the UBA domain involvement are its main genetic characteristics.

Conclusion: Although rare, mutations in SQSTM1 can lead to various clinical subtypes of FTD and FTD-ALS, including the rare combination of PNFA and PBP. Exon missense mutation is the main type of mutation, which is common in the UBA domain.

Keywords: Frontotemporal dementia; Progressive bulbar palsy; Progressive nonfluent aphasia; SQSTM1.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33125541/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons

amyloidorg@gmail.com (Unknown) — Mon, 29 Mar 2021 21:18:00 -0700

Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons

Abstract

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson's disease (PD), clinically representing typical PD.

Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation.

Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons.

Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy.

Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; VPS35; induced pluripotent stem cells; mitochondrial impairment; α-synuclein.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33142012/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ 1-42 -Induced AD-Like Mice and SH-SY5Y Cells

amyloidorg@gmail.com (Unknown) — Mon, 29 Mar 2021 21:17:00 -0700

Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ 1-42 -Induced AD-Like Mice and SH-SY5Y Cells

Abstract

Scope: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome.

Methods and results: AD mice model built through intracerebroventricular injection of Aβ1-42 and AD cell model developed through the SH-SY5Y cell line and Aβ1-42 are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in Aβ1-42 -injected mice and relieves apoptosis in Aβ1-42 -treated SH-SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorates Aβ accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses Aβ1-42 -induced cognitive impairment. Besides, Q3G restores Aβ1-42 -induced reduction of short-chain fatty acids (SCFAs) and gut microbiota dysbiosis.

Conclusion: Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ1-42 -induced cognitive dysfunction.

Keywords: Alzheimer's disease; brain insulin resistance; gut microbiota; inflammation; quercetin-3-O-glucuronide.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33141510/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : L-3-n-Butylphthalide improves synaptic and dendritic spine plasticity and ameliorates neurite pathology in Alzheimer's disease mouse model and cultured hippocampal neurons

amyloidorg@gmail.com (Unknown) — Mon, 29 Mar 2021 21:16:00 -0700

L-3-n-Butylphthalide improves synaptic and dendritic spine plasticity and ameliorates neurite pathology in Alzheimer's disease mouse model and cultured hippocampal neurons

Abstract

Alzheimer's disease (AD) is the most common cause of dementia among elderly people. Despite enormous efforts, the pathogenesis of AD still remains unclear and no drug has yet been proved to be disease-modifying. As the basis of learning and memory, the plasticity of synapse and dendritic spine has been impaired during AD progression. Previous studies have showed a protective effect of L-3-n-butylphthalide (L-NBP) on cognitive deficits in AD, we wonder whether this protective effect is associated with positive alterations on synapse and dendritic spines. In this study, we first of all confirmed the anti-dementia effect of L-NBP in 13-month-old APP/PS1 mice, and then investigated the alterations in synaptic and dendritic spine plasticity due to L-NBP treatment both in vivo and in vitro. We also conducted preliminary studies and found the possible mechanisms related to the inhibition of over-activated complement cascade and the remodeling of actin cytoskeleton. Besides, we also found extra benefits of L-NBP on presynaptic dystrophic neurites and attempted to give explanations from the view of autophagy regulation. Taken together, our study added some new evidence to the application of L-NBP in AD treatment and provided deeper insight into the relevant mechanisms for future study.

Keywords: Alzheimer's disease; Cognition; Dendritic spine; L-3-n-Butylphthalide (L-NBP); Synapse.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33146400/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Isoform-specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias

amyloidorg@gmail.com (Unknown) — Mon, 29 Mar 2021 21:15:00 -0700

Isoform-specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias

Abstract

Cumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer's disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the post-mortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD, and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β-amyloid, and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human post-mortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.

Keywords: Alzheimer's disease; Fyn kinase; Lewy body dementia; alternative splicing; glial activation; tauopathy.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33128789/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Primary age-related tauopathy (PART) in the general autopsy setting: Not just a disease of the elderly

amyloidorg@gmail.com (Unknown) — Mon, 29 Mar 2021 21:15:00 -0700

Primary age-related tauopathy (PART) in the general autopsy setting: Not just a disease of the elderly

Abstract

Primary age-related tauopathy (PART) is generally considered a diagnosis of the elderly. In this letter, the authors present data showing that the pathologic changes of PART can occur in the general autopsy population significantly earlier than largely reported in the recent literature, particularly in woman.

Keywords: Alzheimer; PART; Tau; dementia; neurodegenerative.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33147361/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Yuan‑zhi‑san inhibits tau protein aggregation in an Aβ 1‑40‑induced Alzheimer's disease rat model via the ubiquitin‑proteasome system

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:20:00 -0800

Yuan‑zhi‑san inhibits tau protein aggregation in an Aβ 1‑40‑induced Alzheimer's disease rat model via the ubiquitin‑proteasome system

Abstract

Yuan‑zhi‑san (YZS) is a classic type of Traditional Chinese Medicine, which has been reported to aid in the treatment of Alzheimer's disease (AD). The present study aimed to investigate the effects of YZS on tau protein aggregation, a hallmark of AD pathology, and its possible mechanisms. The results demonstrated that YZS improved learning and memory abilities, and decreased the severity of AD pathology in β‑amyloid (Aβ1‑40)‑induced AD rats. Moreover, YZS administration inhibited the hyperphosphorylation of tau protein at Ser199 and Thr231 sites. Several vital enzymes in the ubiquitin‑proteasome system (UPS), including ubiquitin‑activating enzyme E1a/b, ubiquitin‑conjugating enzyme E2a, carboxyl terminus of Hsc70‑interacting protein, ubiquitin C‑236 terminal hydrolase L1 and 26S proteasome, were all significantly downregulated in AD rats, which indicated an impaired enzymatic cascade in the UPS. In addition, it was identified that YZS treatment partly increased the expression levels of these enzymes in the brains of AD rats. In conclusion, the present results suggested that YZS could effectively suppress the hyperphosphorylation of tau proteins, which may be partially associated with its beneficial role in restoring functionality of the UPS.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33604685/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating β‑amyloid metabolism‑associated enzymes

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:20:00 -0800

CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating β‑amyloid metabolism‑associated enzymes

Abstract

Alzheimer's disease (AD) is the most common form of dementia that is primarily characterized by progressive cognitive deficits. The toxicity of amyloid β‑protein (Aβ) serves an important role in the progression of AD, resulting in neuronal loss via a number of possible mechanisms, including oxidative stress, mitochondrial dysfunction, energy depletion, apoptosis and neuroinflammation. Previous studies have reported that cocaine amphetamine regulated transcript (CART) treatment improves memory and synaptic structure in APP/PS1 mice. Therefore, the present study aimed to investigate whether CART served a protective role against memory deficits in AD. APP/PS1 mice were treated with CART or PBS. Spatial memory was assessed using the Morris water maze. Oxidative stress and DNA damage were compared among wild‑type, APP/PS1 and CART‑treated APP/PS1 mice. The mRNA and protein expression levels of Aβ metabolism‑associated enzymes, including neprilysin (NEP), insulin‑degrading enzyme (IDE), receptor for advanced glycation end products (RAGE) and low‑density lipoprotein receptor‑related protein 1 (LRP‑1), in the hippocampus were measured via reverse transcription‑quantitative PCR and western blotting, respectively. CART improved the memory impairment of APP/PS1 mice by reducing oxidative stress, inhibiting DNA damage and protecting against mitochondrial dysfunction in the cerebral cortex and hippocampus. CART also reduced cell senescence and oxidative stress in Aβ1‑42‑exposed primary cortical neurons in APP/PS1 mice. Moreover, CART promoted Aβ degradation via modulating Aβ metabolism‑associated enzymes, including IDE, NEP, LRP‑1 and RAGE. Collectively, the present study indicated that CART improved the learning and memory capacity of APP/PS mice, thus may have potential to serve as a novel therapeutic agent for AD.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33604684/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:19:00 -0800

Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Abstract

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient-albeit to a smaller extent-to induce premature distal axonal trafficking deficits and increased DSBs.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33619157/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Exploring new avenues for modifying course of progression of Alzheimer's disease: The rise of natural medicine

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:18:00 -0800

Exploring new avenues for modifying course of progression of Alzheimer's disease: The rise of natural medicine

Abstract

With a constantly growing elderly population worldwide, a focus on developing efficient prevention and therapy for Alzheimer's disease (AD) seems timely and topical. Emphasis on natural medicine is increasingly popular in the search for drug candidates that are capable of preventing and treating AD related pathology, particularly where suppression of amyloid accumulation, neurofibrillary tangle formation, neuroinflammation and oxidative stress are equally significant. A number of phytochemical compounds have been shown to collectively reduce these AD hallmarks with the progression of natural drug candidates into human clinical trials. This review focuses on current research surrounding the therapies emerging within natural medicines and their related therapeutic potential for AD treatment.

Keywords: Alzheimer's disease; Natural medicine; Neuro-inflammation; Oxidative stress.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33607542/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : AAV9-mediated gene delivery of MCT1 to oligodendrocytes does not provide a therapeutic benefit in a mouse model of ALS

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:17:00 -0800

AAV9-mediated gene delivery of MCT1 to oligodendrocytes does not provide a therapeutic benefit in a mouse model of ALS

Abstract

Oligodendrocyte dysfunction has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron loss. The failure of trophic support provided by oligodendrocytes is associated with a concomitant reduction in oligodendroglial monocarboxylate transporter 1 (MCT1) expression and is detrimental for the long-term survival of motor neuron axons. Therefore, we established an adeno-associated virus 9 (AAV9)-based platform by which MCT1 was targeted mostly to white matter oligodendrocytes to investigate whether this approach could provide a therapeutic benefit in the SOD1G93A mouse model of ALS. Despite good oligodendrocyte transduction and AAV-mediated MCT1 transgene expression, the disease outcome of SOD1G93A mice was not altered. Our study further increases our current understanding about the complex nature of oligodendrocyte pathology in ALS and provides valuable insights into the future development of therapeutic strategies to efficiently modulate these cells.

Keywords: adeno-associated virus; amyotrophic lateral sclerosis; gene therapy; monocarboxylate transporter 1; oligodendrocytes.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33614825/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Smallest Secondary Nucleation Competent Aβ Aggregates Probed by an ATP-Independent Molecular Chaperone Domain

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:17:00 -0800

Smallest Secondary Nucleation Competent Aβ Aggregates Probed by an ATP-Independent Molecular Chaperone Domain

Abstract

Protein oligomerization is a commonly encountered strategy by which the functional repertoire of proteins is increased. This, however, is a double-edged sword strategy because protein oligomerization is notoriously difficult to control. Living organisms have therefore developed a number of chaperones that prevent protein aggregation. The small ATP-independent molecular chaperone domain proSP-C BRICHOS, which is mainly trimeric, specifically inhibits fibril surface-catalyzed nucleation reactions that give rise to toxic oligomers during the aggregation of the Alzheimer's disease-related amyloid-β peptide (Aβ42). Here, we have created a stable proSP-C BRICHOS monomer mutant and show that it does not bind to monomeric Aβ42 but has a high affinity for Aβ42 fibrils, using surface plasmon resonance. Kinetic analysis of Aβ42 aggregation profiles, measured by thioflavin T fluorescence, reveals that the proSP-C BRICHOS monomer mutant strongly inhibits secondary nucleation reactions and thereby reduces the level of catalytic formation of toxic Aβ42 oligomers. To study binding between the proSP-C BRICHOS monomer mutant and small soluble Aβ42 aggregates, we analyzed fluorescence cross-correlation spectroscopy measurements with the maximum entropy method for fluorescence correlation spectroscopy. We found that the proSP-C BRICHOS monomer mutant binds to the smallest emerging Aβ42 aggregates that are comprised of eight or fewer Aβ42 molecules, which are already secondary nucleation competent. Our approach can be used to provide molecular-level insights into the mechanisms of action of substances that interfere with protein aggregation.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33621049/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Secondary Structures of Proteins: A Comparison of Models and Experimental Results

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:15:00 -0800

Secondary Structures of Proteins: A Comparison of Models and Experimental Results

Abstract

Secondary structure predictions of proteins were compared to experimental results by wide-line 1H NMR. IUPred2A was used to generate predictions of disordered protein or binding regions. Thymosin-β4 and the stabilin-2 cytoplasmic domain were found to be mainly disordered, in agreement with the experimental results. α-Synuclein variants were predicted to be disordered, as in the experiments, but the A53T mutant showed less predicted disorder, in contrast with the wide-line 1H NMR result. A disordered binding site was found for thymosin-β4, whereas the stabilin-2 cytoplasmic domain was indicated as such in its entire length. The last third of the α-synuclein variant's sequence was a disordered binding site. Thymosin-β4 and the stabilin-2 cytoplasmic domain contained only coils and helices according to five secondary structure prediction methods (SPIDER3-SPOT-1D, PSRSM, MUFold-SSW, Porter 5, and RaptorX). β-Sheets are present in α-synucleins, and they extend to more amino acid residues in the A53T mutant according to the predictions. The latter is verified by experiments. The comparison of the predictions with the experiments suggests that helical parts are buried.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33620224/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Mechanistic Insights into the Co-Aggregation of Aβ and hIAPP: An All-Atom Molecular Dynamic Study

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:14:00 -0800

Mechanistic Insights into the Co-Aggregation of Aβ and hIAPP: An All-Atom Molecular Dynamic Study

Abstract

Patients with Alzheimer's disease (AD) have a high risk of developing Type II diabetes (T2D). The co-aggregation of the two disease-related proteins, Aβ and hIAPP, has been proposed as a potential molecular mechanism. However, the detailed Aβ-hIAPP interactions and structural characteristics of co-aggregates are mostly unknown at atomic level. Here, we explore the conformational ensembles of the Aβ-hIAPP heterodimer and Aβ or hIAPP homodimer by performing all-atom explicit-solvent replica exchange molecular dynamic simulations. Our simulations show that the interaction propensity of Aβ-hIAPP in the heterodimer is comparable with that of Aβ-Aβ/hIAPP-hIAPP in the homodimer. Similar hot spot residues of Aβ/hIAPP in the homodimer and heterodimer are identified, indicating that both Aβ and hIAPP have similar molecular recognition sites for self-aggregation and co-aggregation. Aβ in the heterodimer possesses three high β-sheet probability regions: the N-terminal region E3-H6, the central hydrophobic core region K16-E22, and the C-terminal hydrophobic region I31-A41, which is highly similar to Aβ in the homodimer. More importantly, in the heterodimer, the regions E3-H6, F19-E22, and I31-M35 of Aβ and the amyloid core region N20-T30 of hIAPP display higher β-sheet probability than they do in homodimer, implying their crucial roles in the formation of β-sheet-rich co-aggregates. Our study sheds light on the co-aggregation of Aβ and hIAPP at an atomic level, which will be helpful for an in-depth understanding of the molecular mechanism for epidemiological correlation of AD and T2D.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33616398/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Peptidomimetic-Based Vesicles Inhibit Amyloid-β Fibrillation and Attenuate Cytotoxicity

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:12:00 -0800

Peptidomimetic-Based Vesicles Inhibit Amyloid-β Fibrillation and Attenuate Cytotoxicity

Abstract

An interruption in Aβ homeostasis leads to the deposit of neurotoxic amyloid plaques and is associated with Alzheimer's disease. A supramolecular strategy based on the assembly of peptidomimetic agents into functional vesicles has been conceived for the simultaneous inhibition of Aβ42 fibrillation and expedited clearance of Aβ42 aggregates. Tris-pyrrolamide peptidomimetic, ADH-353, contains one hydrophobic N-butyl and two hydrophilic N-propylamine side chains and readily forms vesicles under physiological conditions. These vesicles completely rescue both mouse neuroblastoma N2a and human neuroblastoma SH-SY5Y cells from the cytotoxicity that follows from Aβ42 misfolding likely in mitochondria. Biophysical studies, including confocal imaging, demonstrate the biocompatibility and selectivity of the approach toward this aberrant protein assembly in cellular milieu.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33600171/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer's Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:11:00 -0800

Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer's Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

Abstract

Lactulose, as a prebiotic, can be utilized by human gut microbiota and stimulate their growth. Although microbiota modulation has become an emerging approach to manage many diseases and can be achieved by the administration of prebiotics, fewer investigations have been carried out on the therapeutic mechanism of lactulose. Two trehalose analogs, lactulose and melibiose, were identified as having a neuroprotective effect in polyglutamine and Parkinson disease models. In this study, we examined lactulose and melibiose in a mouse primary hippocampal neuronal culture under the toxicity of oligomeric Aβ25-35. Lactulose was further tested in vivo because its effective concentration is lower than that of melibiose. Lactulose and trehalose were applied individually to mice before a bilateral intrahippocampal CA1 injection of oligomeric Aβ25-35. The administration of lactulose and trehalose attenuated the short-term memory and the learning retrieval of Alzheimer's disease (AD) mice. From a pathological analysis, we found that the pretreatment of lactulose and trehalose decreased neuroinflammation and increased the levels of the autophagic pathways. These results suggest that the neuroprotective effects of both lactulose and trehalose are achieved through anti-inflammation and autophagy. In addition, lactulose was better than trehalose in the enhancement of the synaptic protein expression level in AD mice. Therefore, lactulose could potentially be developed into a preventive and/or therapeutic disaccharide for AD.

Keywords: Alzheimer's disease; autophagy; lactulose; prebiotics; trehalose.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33617267/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Unfolded and intermediate states of PrP play a key role in the mechanism of action of an antiprion chaperone

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:10:00 -0800

Unfolded and intermediate states of PrP play a key role in the mechanism of action of an antiprion chaperone

Abstract

Prion and prion-like diseases involve the propagation of misfolded protein conformers. Small-molecule pharmacological chaperones can inhibit propagated misfolding, but how they interact with disease-related proteins to prevent misfolding is often unclear. We investigated how pentosan polysulfate (PPS), a polyanion with antiprion activity in vitro and in vivo, interacts with mammalian prion protein (PrP) to alter its folding. Calorimetry showed that PPS binds two sites on natively folded PrP, but one PPS molecule can bind multiple PrP molecules. Force spectroscopy measurements of single PrP molecules showed PPS stabilizes not only the native fold of PrP but also many different partially folded intermediates that are not observed in the absence of PPS. PPS also bound tightly to unfolded segments of PrP, delaying refolding. These observations imply that PPS can act through multiple possible modes, inhibiting misfolding not only by stabilizing the native fold or sequestering natively folded PrP into aggregates, as proposed previously, but also by binding to partially or fully unfolded states that play key roles in mediating misfolding. These results underline the likely importance of unfolded states as critical intermediates on the prion conversion pathway.

Keywords: energy landscape; optical tweezers; pharmacological chaperone; protein misfolding.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33619087/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:09:00 -0800

TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau

Abstract

Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.

Keywords: Alzheimer's disease; RNA binding proteins; fibrillar tau; liquid–liquid phase separation (LLPS); oligomeric tau.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33619090/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aβ 1-42-induced mouse model of Alzheimer's disease

amyloidorg@gmail.com (Unknown) — Thu, 11 Mar 2021 21:09:00 -0800

Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aβ 1-42-induced mouse model of Alzheimer's disease

Abstract

Background: Rosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation.

Purpose and study design: The present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aβ1-42-induced mouse model of AD.

Methods: BALB/c mice were divided into ten groups. Half were injected with Aβ1-42 in the hippocampus through stereotaxic surgery to generate the disease groups. The other half received control injections. Each set of five groups were administered orally with vehicle, an ethanolic extract of R. officinalis, ursolic acid, rosmarinic acid or donepezil. Behavior analysis included the Morris water maze test, the novel object recognition test and the Elevated plus maze. The mice were then sacrificed and the hippocampal tissue was processed for immunohistochemistry and gene expression analysis.

Results: The results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aβ1-42. The neuronal density and the expression levels of neurogenic (Ki67, NeuN and DCX) and synaptic (Syn I, II, III, Synaptophysin and PSD-95) markers were also normalized upon treatment with rosmarinic and ursolic acid.

Conclusion: Our findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aβ1-42-induced neurotoxicity in AD.

Keywords: Alzheimer's disease; Neurodegeneration; Neurogenesis; Neurotoxicity; Rosmarinic acid; Ursolic acid.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33601255/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Considering the APOE locus in Alzheimer's disease polygenic scores in the Health and Retirement Study: a longitudinal panel study

amyloidorg@gmail.com (Unknown) — Tue, 9 Mar 2021 22:25:00 -0800

Considering the APOE locus in Alzheimer's disease polygenic scores in the Health and Retirement Study: a longitudinal panel study

Abstract

Background: Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer's disease, which have a strong and well-established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample.

Methods: Here we examine the association between polygenic scores for Alzheimer's disease both with and without the APOE region (chr19: 45,384,477 to 45,432,606, build 37/hg 19) at different P value thresholds and dementia. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score-dementia association in the Health and Retirement Study using generalized linear models accounting for repeated measures by individual and use a binomial distribution, logit link, and unstructured correlation structure.

Results: In a large sample of European ancestry participants of the Health and Retirement Study (n = 9872) with an average of 5.2 (standard deviation 1.8) visit spaced two years apart, we found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We also found that a polygenic score with a P value threshold of 0.01 had the strongest association with the odds of dementia in this sample (odds ratio = 1.10 95%CI 1.0 to 1.2).

Conclusion: We recommend removing the APOE region from polygenic score calculation and treating the APOE locus as an independent covariate when modeling dementia. We also recommend using a moderately conservative P value threshold (e.g. 0.01) when creating polygenic scores for Alzheimer's disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer's disease.

Keywords: Alzheimer's disease; Apolipoprotein E; Dementia; P-value; Polygenic score; Thresholding.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33143703/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Computational Analysis of Alzheimer Amyloid Plaque Composition in 2D- and Elastically Reconstructed 3D-MALDI MS Images

amyloidorg@gmail.com (Unknown) — Tue, 9 Mar 2021 22:24:00 -0800

Computational Analysis of Alzheimer Amyloid Plaque Composition in 2D- and Elastically Reconstructed 3D-MALDI MS Images

Abstract

MALDI mass spectrometry imaging (MSI) enables label-free, spatially resolved analysis of a wide range of analytes in tissue sections. Quantitative analysis of MSI datasets is typically performed on single pixels or manually assigned regions of interest (ROIs). However, many sparse, small objects such as Alzheimer's disease (AD) brain deposits of amyloid peptides called plaques are neither single pixels nor ROIs. Here, we propose a new approach to facilitate the comparative computational evaluation of amyloid plaque-like objects by MSI: a fast PLAQUE PICKER tool that enables a statistical evaluation of heterogeneous amyloid peptide composition. Comparing two AD mouse models, APP NL-G-F and APP PS1, we identified distinct heterogeneous plaque populations in the NL-G-F model but only one class of plaques in the PS1 model. We propose quantitative metrics for the comparison of technical and biological MSI replicates. Furthermore, we reconstructed a high-accuracy 3D-model of amyloid plaques in a fully automated fashion, employing rigid and elastic MSI image registration using structured and plaque-unrelated reference ion images. Statistical single-plaque analysis in reconstructed 3D-MSI objects revealed the Aβ1-42Arc peptide to be located either in the core of larger plaques or in small plaques without colocalization of other Aβ isoforms. In 3D, a substantially larger number of small plaques were observed than that indicated by the 2D-MSI data, suggesting that quantitative analysis of molecularly diverse sparsely-distributed features may benefit from 3D-reconstruction. Data are available via ProteomeXchange with identifier PXD020824.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33138378/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Prediction of amyloid β PET positivity using machine learning in patients with suspected cerebral amyloid angiopathy markers

amyloidorg@gmail.com (Unknown) — Tue, 9 Mar 2021 22:24:00 -0800

Prediction of amyloid β PET positivity using machine learning in patients with suspected cerebral amyloid angiopathy markers

Abstract

Amyloid-β(Aβ) PET positivity in patients with suspected cerebral amyloid angiopathy (CAA) MRI markers is predictive of a worse cognitive trajectory, and it provides insights into the underlying vascular pathology (CAA vs. hypertensive angiopathy) to facilitate prognostic prediction and appropriate treatment decisions. In this study, we applied two interpretable machine learning algorithms, gradient boosting machine (GBM) and random forest (RF), to predict Aβ PET positivity in patients with CAA MRI markers. In the GBM algorithm, the number of lobar cerebral microbleeds (CMBs), deep CMBs, lacunes, CMBs in dentate nuclei, and age were ranked as the most influential to predict Aβ positivity. In the RF algorithm, the absence of diabetes was additionally chosen. Cut-off values of the above variables predictive of Aβ positivity were as follows: (1) the number of lobar CMBs > 16.4(GBM)/14.3(RF), (2) no deep CMBs(GBM/RF), (3) the number of lacunes > 7.4(GBM/RF), (4) age > 74.3(GBM)/64(RF), (5) no CMBs in dentate nucleus(GBM/RF). The classification performances based on the area under the receiver operating characteristic curve were 0.83 in GBM and 0.80 in RF. Our study demonstrates the utility of interpretable machine learning in the clinical setting by quantifying the relative importance and cutoff values of predictive variables for Aβ positivity in patients with suspected CAA markers.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33139780/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : Secondhand smoking and neurological disease: a meta-analysis of cohort studies

amyloidorg@gmail.com (Unknown) — Tue, 9 Mar 2021 22:23:00 -0800

Secondhand smoking and neurological disease: a meta-analysis of cohort studies

Abstract

Background The results of studies on the relationship between secondhand smoking and neurological disease remain controversial. We conducted a meta-analysis to explore the association between secondhand smoking and risk of neurological disease. Methods Literature search was performed in PubMed, Embase and Web of Science through December 2019. We included cohort studies which examined the association between secondhand smoking and risk of neurological disease. According to the type of neurological disease, summary relative risks (RRs) with 95% confidence intervals (CIs) of stroke, cognitive impairment and Parkinson disease (PD) for secondhand smoking exposure were calculated. Results A total of 14 unique articles (n=697,185 participants) were eventually included in the analysis. When all studies were pooled, the RR of stroke for secondhand smoking exposure was 1.20 (95% CI: 1.04, 1.38). When studies included only non-smokers, the pooled RR of stroke was 1.20 (95% CI: 1.05, 1.37). Summary RRs of cognitive impairment and PD for secondhand smoking exposure were 1.43 (95% CI: 1.02, 2.00) and 0.83 (95% CI: 0.72, 0.95), respectively. Summary RRs did not change significantly when excluding one study at a time. Conclusions Secondhand smoking was found to be positively associated with risks of stroke and cognitive impairment, while inversely associated with risk of PD. Overall, our finding is a reminder of the need to step up smoking bans to prevent health damage, and also suggests that more researches on biological mechanisms whereby secondhand smoking affect PD may be beneficial to PD prevention and treatment.

Keywords: meta-analysis; neurological disease; risk; secondhand smoking

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33128528/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.

Beta Amyloid Peptide: Research Paper : APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids

amyloidorg@gmail.com (Unknown) — Tue, 9 Mar 2021 22:22:00 -0800

APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids

Abstract

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33139712/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.