The elevation and accumulation of soluble amyloid ?-peptide (A?) oligomers closely correlate with cognitive decline and/or disease progression in Alzheimer's disease (AD). Furthermore, at the cellular level, A? oligomers induce synaptic dysfunction, including the impairment of long-term potentiation (LTP), an electrophysiological correlate of learning and memory in the mammalian hippocampus. Our preliminary studies showed that A? oligomers, the A? species known to trigger synaptic dysfunction, caused a profound 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? oligomers 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 +/-), the main PI(4,5)P2 phosphatase [PI(4,5)P2 degrading enzyme] in the brain and synapses. Furthermore, the characterized inhibitory effect of A? on LTP was strongly suppressed in brain slices from the Synj1 +/- mice. Thus, based our robust preliminary studies, we hypothesize that inhibition of Synj1, which is mainly responsible for PI(4,5)P2 turnover at the synapse, and corresponding increases in a specific pool of PI(4,5)P2 in neurons may ameliorate A?-induced synaptic dysfunctions. Synj1 is expressed and concentrated at the synapse in the brain regions known to be vulnerable in AD. Additionally, it is reasonable to postulate that Synj1 is a druggable target, given the fact that SHIP2, an enzyme in the same lipid phosphatase family, is a validated therapeutic target in diabetes. These facts validate Synj1 as a promising druggable target in AD and we intend to determine if small molecule inhibitors of Synj1 can be potential therapeutic agents in AD. To this end, we will attempt to identify novel small molecule Synj1 inhibitors and determine if these compounds can prevent or reverse A?-associated synaptic abnormalities. Our specific goals will be to identify novel small molecule inhibitors of Synj1 by i) developing a mid to high throughput enzyme assay, ii) screening small molecule libraries with the assay, iii) performing preliminary medicinal chemistry on hit compounds and iv) testing the biological activity of the resulting compounds and derivatives in secondary cell-based assays. Successful completion of this work will yield active lead compounds that can be further developed as effective therapeutic agents in AD.
Synaptic dysfunction caused by amyloid ?-peptide (A?) has been linked to cognitive deficits in AD. Synaptojanin 1 (Synj1) is a lipid phosphatase that is highly expressed in the brain and the reduced Synj1 levels ameliorate A?-induced synaptic dysfunction, suggesting Synj1 as a therapeutic target in AD. Our proposed study will identify novel, small molecule inhibitors of Synj1. Successful completion of this work will yield active lead compounds that can be further developed as an effective therapeutic agent in AD.
| Di Paolo, Gilbert; Kim, Tae-Wan (2011) Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 12:284-96 |
