Mechanisms of Protein Seeding in Neurodegenerative Diseases

Walker, Lary C.; Diamond, Marc I.; Duff, Karen; Hyman, Bradley T.

doi:10.1001/jamaneurol.2013.1453

Cited by 203 publications

(169 citation statements)

References 32 publications

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“…While much research effort has been put toward determining tau aggregate structure, aggregation kinetics (Von Bergen et al , 2005), templated misfolding, and pathological toxicity of tau in the diseased brain (Walker et al , 2013), two extremely important questions remain unclear: What triggers the very initial aggregation of tau? And which mechanism underlies the switch from functional soluble tau in a healthy neuron toward aberrantly pathologically folded soluble tau, and fibrillary tau accumulating in NFTs?…”

Section: Discussionmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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“…78 Indeed, such a prion-like mechanism of endogenous templated protein corruption was suggested as a common mechanism for multiple neurodegenerative diseases. 85 Additional Ab-mediated mechanisms may also contribute to propagation of AD pathology; for example, oligomer binding to membrane lipids or to a7 nicotinic cholinergic receptors might modulate the downstream signaling. 84,86,87 Our results suggest that effective therapies will need to target synaptic Ab oligomers and that antiamyloid therapies will be much less effective once synaptic p-tau pathology has developed, thus providing a potential explanation for the failure of amyloid-based trials.…”

Section: Amyloid-b Precedes P-tau In Ad Synapsesmentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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“…Several studies screened small collections of FDA-approved drugs to identify new compounds harboring antiaggregation effects [34,35]. One promising area of research will be to screen AD-associated phenotypes involving transcellular propagation of tau or Aβ aggregates in the manner shared with that of prion [36,37]. Given increasing significance of cell-to-cell propagation of AD-associated protein aggregates [36,37], modeling an emerging but potentially significant pathological phenotype is likely to yield new opportunities for discovering highly effective drug repositioning candidates.…”

Section: Phenotypic Approachesmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Mechanisms of Protein Seeding in Neurodegenerative Diseases

Cited by 203 publications

References 32 publications

Tau protein liquid–liquid phase separation can initiate tau aggregation

Tau protein liquid–liquid phase separation can initiate tau aggregation

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

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