Hippocampal Disruptions of Synaptic and Astrocyte Metabolism are Primary Events of Early Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease

Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes brain energy metabolism arise the preclinical phase of AD, suggesting important metabolic component early AD pathology. Neurons astrocytes function close collaboration, which essential for recycling neurotransmitters synapse. However, this crucial interplay during stages development has not been sufficiently investigated. Here, we provide integrative analysis cellular Aβ cortex hippocampus 5xFAD mouse model AD. Our electrophysiological examination revealed increase spontaneous excitatory signaling hippocampus. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle mapped stable 13C isotope tracing. Particularly, reduced astrocyte activity led to glutamine synthesis, turn hampering GABA synthesis In contrast, mice displayed elevated capacity oxidative glucose a compensation. We found limited changes when explored proteome metabolome mice, supporting that functional disturbances between neurons are primary events addition, synaptic mitochondrial glycolytic was impaired selectively hippocampus, whereas non-synaptic maintained. These findings were supported ultrastructural analyses demonstrating disruptions morphology, particularly Collectively, our study reveals complex regional cell-specific adaptations, amyloid pathology, may be fundamental progressing dysfunction