Early mitochondrial dysfunction proceeds neuroinflammation, synaptic alteration, and autophagy impairment in hippocampus ofAppknock-in Alzheimer mouse models

Abstract

ABSTRACTIncreased amyloid β-peptide (Aβ) level is one of the drivers of Alzheimer’s disease (AD). Amyloid precursor protein (App) knock-in mice recapitulate the human Aβ pathology, allowing the elucidation of the downstream effects of Aβ and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in theAppNL-FandAppNL-G-Fknock-in mouse models by time-course transcriptome analysis of the hippocampus, a region severely affected in AD. Energy metabolism emerged as one of the most significantly altered pathways at an early stage of the development of the pathologies. Functional experiments in mitochondria isolated fromAppNL-G-Fbrain subsequently identified upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, combined with higher susceptibility to Ca2+-overload. This was followed by a strong neuroinflammatory response and impaired autophagy. Accumulation of autophagosomes and reduced number of mitochondria content in presynaptic terminals could account for the altered synapse morphology including increased number of synaptic vesicles and lowered thickness of post synaptic density inAppNL-G-Fmice. This shows that Aβ-induced pathways in theAppknock-in mice recapitulate some key pathologies observed in AD brain, and our data herein contributes to the understanding of their timewise appearance and potential role in new therapeutic approaches.