APP Gene Dose-Mediated Dysregulation of the Endolysosomal Network Acts to Compromise Synaptic Structure and Function Leading to Alzheimer’s Disease in Down Syndrome

Synapse loss is a critical manifestation of Alzheimer’s disease (AD) pathogenesis that results in progressive cognitive decline. Accordingly, interventions targeting synaptic changes may prevent or reverse cognitive decline and neurodegeneration. However, mechanisms that initiate synapse loss are poorly understood. People with Down syndrome (DS) are at increased risk of AD, a disorder referred to as DS-AD. Data from humans and mouse models of DS-AD demonstrate that an extra copy of the Amyloid Precursor Protein (APP) gene is necessary for AD in those with DS. Additional studies indicate that dysregulation in the cellular endolysosomal network (ELN) is an early manifestation in both AD and DS that could contribute to synapse loss; however, underlying mechanisms remain unknown. Moreover, while age is a significant risk factor for DS-AD, how age-related events intersect with pathogenic mechanisms, including those leading to synapse failure, are poorly understood. Building on preliminary studies in which we defined the mechanism by which increased APP gene dose induces ELN dysregulation, we propose to test the hypothesis that increased APP gene dose-mediated dysregulation of the ELN acts age-dependently to compromise synaptic structure and function in DS-AD. In exploratory studies we test the subsidiary hypothesis that ELN dysregulation-induced senescence contributes to synapse failure and loss. Understanding the mechanism(s) responsible for synapse failure could support the discovery of interventions targeting this critical disease manifestation.