Tau protein aggregation is a hallmark of Alzheimer’s disease (AD) brains and additional tauopathies including frontotemporal lobar degeneration (FTLD). Substantial evidence has been linking Tau to neurodegeneration, but the mechanisms are still incompletely understood. Tau impacts mitochondrial function and dynamics by impairing mitochondrial shaping proteins, leading to neurotoxicity. These proteins are also involved in the endoplasmic reticulum-mitochondria coupling via the mitochondria-associated ER membranes or MAMs. An upregulation of MAMs function is observed in Aβ-related AD models, impairing calcium homeostasis as well as phospholipid and cholesterol metabolism, leading to neuronal death. Interestingly, the influence of Tau on the ER-mitochondria axis remain elusive until today. Thus, we hypothesize that abnormal Tau protein disturbs the ER-mitochondria interaction by affecting the MAMs in a process involving the mitochondrial shaping proteins. The specific aims of this project are to prove this concept and to elucidate in detail the impact of abnormal Tau protein on the ER-mitochondria coupling. We aim to dissect a novel fundamental mechanism using state-of-the-art technology (confocal microscopy, structure illumination microscopy, proximity ligation assay) and functional readouts. Moreover, by different molecular and CRISPR approaches, we will study the ER-mitochondria axis as a potential target in AD. The project has ramifications for additional neurodegenerative diseases such as Parkinson’s disease as well as amyotrophic lateral sclerosis with associated temporal dementia (ALS/FTD) that also have been linked with damaged ER-mitochondria associations.