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.
Original language | English (US) |
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Pages (from-to) | 3499-3509 |
Number of pages | 11 |
Journal | ACS Chemical Neuroscience |
Volume | 11 |
Issue number | 21 |
DOIs | |
State | Published - Nov 4 2020 |
Keywords
- Alzheimer's disease
- SIRT1
- TYROBP
- Tau propagation
- Tau seeding
- extracellular vesicles
- melatonin
- nSMase2
- p300/CBP
ASJC Scopus subject areas
- Cognitive Neuroscience
- Biochemistry
- Physiology
- Cell Biology