Project Summary/Abstract Mutations in the Presenilin (PSEN) genes account for ~90% of all causative mutations in familial Alzheimer's disease (FAD). During the last two decades, our large numbers of genetic studies using conditional knockout and knockin mice have demonstrated that Presenilin (PS) is essential for learning and memory, synaptic function and neuronal survival, and that PSEN1 mutations cause loss of its essential function and g- secretase activity. Our genetic findings are further supported by cell culture and biochemical studies showing that ~90% of PSEN1 mutations cause loss of g-secretase activity. In this renewal application (YEARS 20-24), we propose to extend our successful PS studies to the development of novel therapies for FAD. Specifically, we will perform preclinical studies using recombinant adeno-associated virus to deliver wild-type human PS1 (hPS1) to PS mutant mouse brains and then determine whether hPS1 rescues impaired g-secretase activity, neurodegeneration, synaptic and memory deficits caused by PS mutations (Aim 1). The amyloid precursor protein (APP) was the first protein associated with sporadic AD, and the APP V717I mutation was the first FAD mutation identified. The genetic link of APP mutations to FAD and the presence of amyloid plaques in sporadic AD brains highlight the importance of APP in AD pathogenesis. Despite its importance, APP normal function in the cerebral cortex remains unclear due to genetic redundancy of its family members, APLP1 and APLP2, and perinatal lethality of APP/APLP1/APLP2 triple knockout mice. We therefore propose to investigate the normal physiological role of APP family through the generation and multidisciplinary analysis of APP/APLP1/APLP2 conditional triple knockout mice, in which all APP family members are selectively inactivated in excitatory or inhibitory neurons of the cerebral cortex (Aim 2). Despite the abundance of APP, APLP1 and APLP2 in excitatory neurons of the cerebral cortex, their inactivation does not lead to early lethality, loss of cortical neurons or increases of apoptosis. We will investigate the role of APP family in excitatory and inhibitory neurons and how APP family regulates hippocampal local circuits. The completion of the proposed study will provide preclinical proof-of-concept data on PS based therapy for FAD and shed light on how APP family regulates neuronal excitability and synaptic plasticity in the hippocampal network.