Enhancing Synaptic Autophagy for Neuroprotection in Alzheimer's disease

Synapse loss is an early event in Alzheimer’s disease (AD), which may explain some of the earliest cognitive symptoms seen in these patients. Macroautophagy, herein referred to as autophagy, is a lysosome mediated degradation pathway that plays a specialized role in the synapse and, thus, may be important for learning and memory. Autophagy is also implicated in the pathogenesis of AD. The precise role of autophagy in AD is still unclear, but there is evidence that autophagic processing of synaptic proteins is disrupted in the course of AD. This proposal aims to investigate how AD-associated pathogenesis interferes with synaptic autophagy and if specifically targeting synaptic autophagy can be neuroprotective in an AD mouse model. Aim 1 will utilize primary hippocampal cell cultures derived from the APPNL-F/NL-F mouse model of AD to determine which step in the autophagic processing of synaptic proteins is disrupted by AD-associated pathogenic changes. Aim 2 will evaluate if optimizing synaptic autophagy by over-expressing the proteins Rab26 and/or Bassoon in the mouse brain is protective in APPNL-F/NL-F mice. To pursue these aims, this proposal incorporates biochemical, histochemical, cell biological, genetic, and behavioral approaches in mouse models and primary neuronal cultures. The data collected will provide insight into how AD-associated pathogenic changes contribute to disruption of synaptic autophagy, and if optimizing synaptic autophagy can be protective in AD.