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Article Dans Une Revue (Article De Synthèse) Alzheimer's & Dementia : the Journal of the Alzheimer's Association Année : 2023

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

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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.
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inserm-04364637 , version 1 (27-12-2023)

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Morgane Darricau, Changsong Dou, Remi Kinet, Tao Zhu, Li Zhou, et al.. Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric‐Aβ mediates pathology maturation. Alzheimer's & Dementia : the Journal of the Alzheimer's Association, 2023, 20 (3), pp.1894-1912. ⟨10.1002/alz.13604⟩. ⟨inserm-04364637⟩

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