Tau secretion and propagation: Perspectives for potential preventive interventions in Alzheimer's disease and other tauopathies

Annadurai, Narendran; Sanctis, Juan B. De; Hajdúch, Marián; Das, Viswanath

doi:10.1016/j.expneurol.2021.113756

Cited by 25 publications

(20 citation statements)

References 169 publications

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“…Several forms of pathogenic extracellular tau, either free or vesicle enclosed, are suspected of spreading tau pathology [Reviewed in Ref. 53]. Therefore, therapeutic interventions, such as immunotherapy or small molecules that target extracellular tau, may halt disease progression.…”

Section: Discussionmentioning

confidence: 99%

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

et al. 2021

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Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold na€ ıve tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQI-VYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK-or Cys322-targeting drugs have a reduced potency to cause aggregation of na€ ıve tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK-or Cys322-targeting drugs may act as prophylactic agents against tau seeding.

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Section: Discussionmentioning

confidence: 99%

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

et al. 2021

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“…However, exactly how this extracellular secretion of tau relates to intracellular tau accumulation and NFT formation remains to be elucidated. One plausible mechanism is the cell-to-cell propagation of tau pathology, which is the spreading of tau pathology via extracellular tau secretion followed by the uptake of tau by adjacent cells ( 63 ).…”

Section: Possible Mechanisms Underlying the Bidirectional Relationshi...mentioning

confidence: 99%

Bidirectional Relationship Between Sleep Disturbances and Parkinson's Disease

Minakawa

2022

Front. Neurol.

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Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Both diseases share common clinical and pathological features: the gradual progression of neurological and psychiatric symptoms caused by neuronal dysfunction and neuronal cell death due to the accumulation of misfolded and neurotoxic proteins. Furthermore, both of them are multifactorial diseases in which both genetic and non-genetic factors contribute to the disease course. Non-genetic factors are of particular interest for the development of preventive and therapeutic approaches for these diseases because they are modifiable; of these, sleep is a particularly intriguing factor. Sleep disturbances are highly prevalent among both patients with AD and PD. To date, research has suggested that sleep disturbances are a consequence as well as a risk factor for the onset and progression of AD, which implies a bidirectional relationship between sleep and AD. Whether such a relationship exists in PD is less certain, albeit highly plausible given the shared pathomechanisms. This review examines the current evidence for the bidirectional relationship between sleep and PD. It includes research in both humans and animal models, followed by a discussion of the current understanding of the mechanisms underlying this relationship. Finally, potential avenues of research toward achieving disease modification to treat or prevent PD are proposed. Although further efforts are crucial for preventing the onset and slowing the progress of PD, it is evident that sleep is a valuable candidate target for future interventions to improve the outcomes of PD patients.

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“…Macropinocytosis plays a central role in tau pathology by mediating the internalization of large, insoluble tau aggregates ( Wu et al, 2013 ; Evans et al, 2018 ). Tau aggregates bind to HSPGs on the neuronal surface, triggering macropinocytosis ( Holmes et al, 2013 ; Rauch et al, 2018 ; Annadurai et al, 2021 ). Then, the extension of actin-dependent membrane ruffles engulfs tau aggregates, leading to the formation of macropinosomes.…”

Section: Molecular Mechanisms Of Extracellular Tau Uptakementioning

confidence: 99%

The Fate of Tau Aggregates Between Clearance and Transmission

Seitkazina

Kim

Fagan

et al. 2022

Front. Aging Neurosci.

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Neuronal accumulation of mis-folded tau is the pathological hallmark of multiple neurodegenerative disorders, including Alzheimer’s disease. Distinct from amyloid plaques, which appear simultaneously throughout the brain, tau pathology develops first in a specific brain region and then propagates to neuroanatomically connected brain regions, exacerbating the disease. Due to the implication in disease progression, prevention of tau transmission is recognized as an important therapeutic strategy that can halt disease progression in the brain. Recently, accumulating studies have demonstrated diverse cellular mechanisms associated with cell-to-cell transmission of tau. Once transmitted, mis-folded tau species act as a prion-like seed for native tau aggregation in the recipient neuron. In this review, we summarize the diverse cellular mechanisms associated with the secretion and uptake of tau, and highlight tau-trafficking receptors, which mediate tau clearance or cell-to-cell tau transmission.

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Tau secretion and propagation: Perspectives for potential preventive interventions in Alzheimer's disease and other tauopathies

Cited by 25 publications

References 169 publications

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

Bidirectional Relationship Between Sleep Disturbances and Parkinson's Disease

The Fate of Tau Aggregates Between Clearance and Transmission

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