The Interplay of Neuronal Activity and Synaptic Abnormalities and their Restoration through Mitochondria in Alzheimer's Disease

Summary Alzheimer's disease, a leading cause of dementia, is characterized by synaptic dysfunction and aberrant neural activity contributing to cognitive decline, with mitochondria being an early target of amyloid pathology. This sets off a vicious cycle involving synapses, neural activity, and mitochondria, which may differ depending on age and brain region. This proposal seeks to investigate the interconnectedness of these factors in an age- dependent manner across multiple brain regions. By utilizing mouse models of Alzheimer's disease, the study aims to determine whether modulation of neural activity, synapses, or mitochondria could enhance neural plasticity in amyloidosis. Through a combination of in vivo and ex vivo approaches, the proposal aims to unravel the relationship between neural activity and synaptic abnormalities and test the efficacy of targeting Cyclophilin D, a component of the mitochondrial membrane permeability transition pore, in improving mitochondrial health and reversing synaptic and neural activity deficits.