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

INTRODUCTIONThe "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-beta (A beta) have never been experimentally studied in primates phylogenetically close to humans.METHODSWe 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-A beta.RESULTSPathological 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 A beta injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in A beta co-injected macaques.DISCUSSIONOligomeric-A beta mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading.