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.
Alzheimer's disease is characterized clinically by memory impairment and pathologically by the deposition of amyloid-2 peptide (A2) in the brains of AD patients. Evidence is accumulating which supports the hypothesis that A2 may be a factor in early neuronal dysfunction associated with AD. Specifically, levels of A2 correlate with disease progression in animal models of AD. In the brain, A2 interferes with normal neuronal function by mechanisms that are not yet fully understood. We have recently published data indicating that a specific lipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which regulates key aspects of neural function, is altered after treatment of neurons with A2. Additionally, mice with low levels of a specific lipid phosphatase, synaptojanin 1 (Synj1), responsible for metabolizing PI(4,5)P2, are resistant to A2-induced neuronal dysfunction. We propose to further investigate the role Synj1 in A2-induced neuronal dysfunction by using mutants of Synj1 to probe its function in neurons lacking endogenous Synj1. Additionally, we propose to cross a mouse model of AD with mice lacking one copy of Synj1. Since this genotype was protective in vitro, we expect these mice to have ameliorated AD-associated behavioral deficits in learning and memory tasks. Completion of these studies will determine if Synj1 can be a valid target for future AD therapeutic strategies.
|Kim, Tae-Wan (2015) Drug repositioning approaches for the discovery of new therapeutics for Alzheimer's disease. Neurotherapeutics 12:132-42|
|McIntire, Laura Beth J; Lee, Kyu-In; Chang-Ileto, Belle et al. (2014) Screening assay for small-molecule inhibitors of synaptojanin 1, a synaptic phosphoinositide phosphatase. J Biomol Screen 19:585-94|
|Kang, Min Suk; Baek, Seung-Hoon; Chun, Yoon Sun et al. (2013) Modulation of lipid kinase PI4KII? activity and lipid raft association of presenilin 1 underlies ?-secretase inhibition by ginsenoside (20S)-Rg3. J Biol Chem 288:20868-82|
|McIntire, Laura Beth J; Landman, Natalie; Kang, Min Suk et al. (2013) Phenotypic assays for ?-amyloid in mouse embryonic stem cell-derived neurons. Chem Biol 20:956-67|
|Oh, Hyun Geun; Chun, Yoon Sun; Kim, Yonjung et al. (2012) Modulation of transient receptor potential melastatin related 7 channel by presenilins. Dev Neurobiol 72:865-77|
|McIntire, Laura Beth J; Berman, Diego E; Myaeng, Jennifer et al. (2012) Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. J Neurosci 32:15271-6|
|Di Paolo, Gilbert; Kim, Tae-Wan (2011) Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 12:284-96|