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

Benjamin J. Bell, Medhinee M. Malvankar, Carolyn Tallon, Barbara S. Slusher

Research output: Contribution to journalReview articlepeer-review

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 languageEnglish (US)
Pages (from-to)3499-3509
Number of pages11
JournalACS Chemical Neuroscience
Volume11
Issue number21
DOIs
StatePublished - Nov 4 2020

Keywords

  • Alzheimer's disease
  • SIRT1
  • TYROBP
  • Tau propagation
  • Tau seeding
  • extracellular vesicles
  • melatonin
  • nSMase2
  • p300/CBP

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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