Abstract
The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer’s disease (AD) is not fully understood. Here, we provide direct evidence that Aβ42/40 ratio, not total Aβ 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 β precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with Aβ42/40 ratio. Roles of Aβ42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential Aβ42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high Aβ42/40) cells, not with I47F cells (low Aβ42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the Aβ42/40 ratio in AD therapy.
Highlights
The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer’s disease (AD) is not fully understood
We demonstrate that a high Aβ42/40 ratio is able to induce robust tau phosphorylation even in naïve human neural progenitor cells (hNPCs)-derived neurons lacking FAD mutations using a 3D non-cell-autonomous cell culture model
In this study, we showed that Aβ42/40 ratio, but not total Aβ levels, regulates tau pathology in human neural cells, using multiple 3D human neural cell culture models with single cell-derived clonal AD stem cells
Summary
The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer’s disease (AD) is not fully understood. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid β precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with Aβ42/40 ratio. Naïve hNPCs co-cultured with APP TMD I45F (high Aβ42/40) cells, not with I47F cells (low Aβ42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system These results emphasize the importance of reducing the Aβ42/40 ratio in AD therapy. 1 (PSEN1) genes have been used as a standard AD model to study Aβ plaques and Aβ-driven synaptic/memory deficits These mice do not fully develop NFTs or robust neurodegeneration[5,6,7]. The tau pathology observed in these AD neurons has not been shown to be regulated by either Aβ42 or the Aβ42/40 ratio[13,14,15,16]
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