Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology maturation.

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Authors
Darricau, Morgane 
Dou, Changsong 
Kinet, Remi 
Zhu, Tao 
Zhou, Li 
Abstract

INTRODUCTION: The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-β (Aβ) have never been experimentally studied in primates phylogenetically close to humans. METHODS: We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aβ. RESULTS: Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aβ co-injected macaques. DISCUSSION: Oligomeric-Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. HIGHLIGHTS: This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.

Description

Publication status: Published


Funder: European Union's Horizon 2020 research and innovation program (IMI ‐ IMPRiND)


Funder: Investments for the Future Program IdEx Bordeaux GPR BRAIN‐2030


Funder: Bettencourt‐Schueller Foundation


Funder: UK Dementia Research Institute; doi: http://dx.doi.org/10.13039/501100017510

Keywords
Alzheimer's disease, beta-amyloid, non-human primate, prion-like, tau, tauopathy
Journal Title
Alzheimers Dement
Conference Name
Journal ISSN
1552-5260
1552-5279
Volume Title
Publisher
Wiley
Sponsorship
Wellcome Trust (206248/Z/17/Z)