Validating a Novel Lipid Phosphatase Target in Alzheimer's Disease

DESCRIPTION (provided by applicant): The amyloid ¿-peptide (A¿), which originates from the proteolytic cleavage of amyloid precursor protein (APP), plays a central role in the pathogenesis of Alzheimer's disease (AD). Mounting evidence indicates that different species of A¿, such as A¿ oligomers and fibrils, may contribute to AD pathogenesis via distinct mechanisms at different stages of the disease. Importantly, elevated levels of A¿ oligomers closely correlate with cognitive decline and disease progression in animal models of AD. At the cellular level, A¿ disrupts synaptic plasticity, including the impairment of long-term potentiation (LTP), an electrophysiological correlate of learning and memory in the mammalian hippocampus. Our recently published work demonstrated that A¿ oligomers caused a decrease in the levels of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a phospholipid that regulates key aspects of neural function. The destabilizing effect of A¿ on PI(4,5)P2 metabolism was not observed in neurons derived from mice containing higher brain levels of PI(4,5)P2 levels owing to the hemizygous deletion of synaptojanin 1 (Synj1 +/-). Synj1 is the main PI(4,5)P2 phosphatase [PI(4,5)P2 degrading enzyme] in the brain and synapses. Furthermore, the well characterized inhibitory effect of A¿ on LTP was strongly suppressed in brain slices from the Synj1 +/- mice. Furthermore, our preliminary results showed that A¿-induced suppression of phosphorylation of cAMP response element-binding protein (CREB), a critical transcription factor associated with synaptic plasticity and memory, was absent in primary neurons derived from Synj1+/- mice. Thus, based on these results, we hypothesize that inhibition of Synj1 may ameliorate A¿-induced synaptic dysfunction and memory impairment in AD. To this end, the main goals of this proposal are to employ biochemical and mouse genetic approaches to investigate the role of Synj1 in A¿-induced disruption of neuronal signaling and further validate Synj1 as a therapeutic target using cultured neurons and in vivo mouse models of AD. Specifically, we will investigate the role of Synj1 in A¿2-induced alterations in neuronal signaling, and will also determine if hemizygous deletion of Synj1 can ameliorate learning and memory impairments in an animal model of AD. Thus, our study will establish Synj1 as a validated target based on a molecular and system level target characterization study. Successful completion of this work will establish a solid rationale for the development of small molecule inhibitors that could selectively target Synj1, as potential therapeutic agents in AD.