Amyloid-driven tau accumulation on mitochondria potentially leads to cognitive deterioration in alzheimer’s disease

Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.We gratefully acknowledge grant funding support from Ministry of Science and Innovation (MINECO) with exp. PID2019-104921RB-I00/MCI/AEI/10.13039/501100011033 as well as to the Foundation for Applied Medical Research, the University of Navarra (Pamplona, Spain) for financial support and the Asociación de Amigos of the University of Navarra for the grant to M.P.-G. and S.B. We also gratefully acknowledge grant funding support from Spanish Ministerio de Economía y Competitividad (RTI2018-095812-B-I00 MCIN/ AEI/10.13039/501100011033) y por FEDER una manera de hacer Europa and Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000229) to RL, from the Spanish Ministry of Science Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) to J.F.-I. and E.S and from the Department of Economic and Business Development from Government of Navarra (INNOLFACT project; Ref. 0011-1411-2020-000028)