The amyloid hypothesis of Alzheimer's disease at 25 years
Dennis J. Selkoe,John Hardy +1 more
TLDR
In a recent study, this article showed that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years.Abstract:
Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer9s disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down9s syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients9 brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.read more
Citations
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Journal ArticleDOI
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
Justin M. Long,David M. Holtzman +1 more
TL;DR: Recent advances in the understanding of AD pathobiology are reviewed and current treatment strategies are discussed, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.
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How neuroinflammation contributes to neurodegeneration.
TL;DR: Observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders, because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation.
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Oxidative stress and the amyloid beta peptide in Alzheimer's disease.
Clémence Cheignon,M. Tomas,M. Tomas,Dominique Bonnefont-Rousselot,Peter Faller,Christelle Hureau,Christelle Hureau,Fabrice Collin,Fabrice Collin +8 more
TL;DR: This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage, along with the implication of metal ions in AD.
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Ageing as a risk factor for neurodegenerative disease.
Yujun Hou,Xiuli Dan,Mansi Babbar,Yong Wei,Steen G. Hasselbalch,Deborah L. Croteau,Vilhelm A. Bohr,Vilhelm A. Bohr +7 more
TL;DR: Hallmarks of ageing — genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication — correlate with susceptibility to neurodegenerative disease.
Journal ArticleDOI
Gut microbiome alterations in Alzheimer's disease.
Nicholas M. Vogt,Robert L. Kerby,Kimberly A. Dill-McFarland,Sandra Harding,Andrew P. Merluzzi,Sterling C. Johnson,Cynthia M. Carlsson,Sanjay Asthana,Henrik Zetterberg,Kaj Blennow,Kaj Blennow,Barbara B. Bendlin,Federico E. Rey +12 more
TL;DR: The gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals, which adds AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.
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