Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease

Amy M Pooler, Manuela Polydoro, Eduardo A Maury, Samantha B Nicholls, Snigdha M Reddy, Susanne Wegmann, Christopher William, Lubna Saqran, Ozge Cagsal-Getkin, Rose Pitstick, David R Beier, George A Carlson, Tara L Spires-Jones, Bradley T Hyman

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

INTRODUCTION: In early stages of Alzheimer's disease (AD), neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex. This observation from human neuropathological studies led us to pose two alternative hypotheses: that amyloid in the cortex is permissive for the spread of tangles from the medial temporal lobe, or that these are co-occurring but not causally related events simply reflecting progression of AD pathology.

RESULTS: We now directly test the hypothesis that cortical amyloid acts as an accelerant for spreading of tangles beyond the medial temporal lobe. We crossed rTgTauEC transgenic mice that demonstrate spread of tau from entorhinal cortex to other brain structures at advanced age with APP/PS1 mice, and examined mice with either NFTs, amyloid pathology, or both. We show that concurrent amyloid deposition in the cortex 1) leads to a dramatic increase in the speed of tau propagation and an extraordinary increase in the spread of tau to distal brain regions, and 2) significantly increases tau-induced neuronal loss.

CONCLUSIONS: These data strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD.

Original languageEnglish
Pages (from-to)14
JournalActa Neuropathologica Communications
Publication statusPublished - 24 Mar 2015


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