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Sowing the Seeds of Discovery: Tau-Propagation Models of Alzheimer's Disease.

Abstract：

:The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo. Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Bell BJ,Malvankar MM,Tallon C,Slusher BS

doi

10.1021/acschemneuro.0c00531

subject

Has Abstract

pub_date

2020-11-04 00:00:00

pages

3499-3509

issue

21

issn

1948-7193

journal_volume

11

pub_type

杂志文章

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