Perturbed mitochondria-ER contacts in live neurons modelling Alzheimer's disease amyloid pathology

Reports using fixed fibroblasts from familial and sporadic Alzheimer's disease (AD) patients indicated upregulated mitochondria-endoplasmic reticulum contacts (MERC) as a hallmark of AD. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERC in hippocampal neurons from McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like amyloid pathology. Live FRET imaging in Tg revealed perturbed “lipid-MERC” (gap width <10 nm) while “Ca²⁺-MERCs” (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the percentage of lipid-MERC/Total MERC or lipid-MERCs/mitochondria number; however, the average length of lipid-MERC was significantly decreased in Tg as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decrements in the levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of Tg mitochondria. Thus, our results reveal in AD-related neurons changes in MERC structure coupled with impaired mitochondrial functions.