Amyloid-?42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease.

ABSTRACT: The relationship between amyloid-? (A?) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that A?42/40 ratio, not total A? level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid ? precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with A?42/40 ratio. Roles of A?42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential A?42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high A?42/40) cells, not with I47F cells (low A?42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the A?42/40 ratio in AD therapy.

SUBMITTER: Kwak SS 

PROVIDER: S-EPMC7070004 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature