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TRANSCRIPTOME ANALYSIS OF HIPPOCAMPUS OF APP KNOCK-IN ALZHEIMER MOUSE MODELS REVEALS AUTOPHAGY IMPAIRMENT LINKED WITH SYNAPTIC DYSFUNCTION
Abstract
Aims
Alzheimer Disease (AD) is a neurodegenerative disorder characterized by impaired protein homeostasis. Autophagy is a major clean up system which is impaired in AD leading to an increase of autophagosomes in dystrophic neurites. The aim of this study is to understand the development of autophagy impairment associated with Aβ deposition and the link between autophagy impairment and other AD related pathologies.
Methods
We performed RNA-sequencing analysis of hippocampus from App knock-in mouse models at three different ages to compare and evaluate the early as well as the more advanced stages of neuropathological changes. Autophagy flux was measured in the crude synaptosomal fractionations of hippocampus, and autophagosome accumulation was investigated by immunofluorescence (IF) staining and electron microscopy. We also performed IF staining of tau in autophagy-deficient mouse brain.
Results
We sequenced approximately 46,000 transcripts. Pathway analysis revealed that pathways regulating autophagy were slightly up-regulated before onset of pathology, and it gradually decreased at late stage in AppNL-G-F mice mimicking the processes present in AD brain. We found an accumulation of autophagosomes in 12-months-old AppNL-G-F mice but not in 2-months-old. Interestingly, swollen synapses containing autophagosomes were observed in 12-months-old AppNL-G-Fmice. It may indicate a link between autophagy impairment and synaptic dysfunction. We also revealed phosphorylated tau accumulation in hippocampus of autophagy-deficient mice.
Conclusions
We revealed autophagy impairment in App knock-in mouse models. Autophagy impairment may have a link with other AD related pathologies such as synaptic dysfunction and tau pathology.