Chronic optogenetic activation of hippocampal CA1 neurons triggers Alzheimer’s disease-like proteomic remodeling

Neuronal overexcitability triggers synaptic changes, leading to neural hyperactivity, network disruption, and is postulated to trigger neurodegeneration in Alzheimer’s disease (AD). However, the sequence of synaptic changes from excessive activity remains unclear. We employed optogenetics to induce sustained neuronal hyperactivity in the hippocampi of wild-type and AD-like 5xFAD mice. After a month of daily optogenetic stimulation, the proteomic profiles of photoactivated wild-type and 5xFAD mice exhibited remarkable similarity. Proteins involved in translation, protein transport, autophagy, and notably in the AD pathology were upregulated in wild-type mice. Conversely, both glutamatergic and GABAergic synaptic proteins were downregulated. These hippocampal proteomic and signaling alterations in wild-type mice resulted in spatial memory loss and augmented Αβ42 secretion. Collectively, these findings indicate that sustained neuronal hyperactivity alone replicates proteome changes seen in AD-like mutant mice. Therefore, prolonged neuronal hyperactivity may contribute to synaptic transmission disruption, memory deficits and the neurodegenerative process associated with AD.