Due to the critical role of gamma-secretase in the generation of A? peptides, which are believed to be essential in Alzheimer's disease (AD) pathogenesis, gamma-secretase inhibitors have emerged as potential drug targets for AD. However, the wide spectrum of gamma-secretase substrates and the differential activities of the two major A? species, A?40 and A?42, in amyloid pathology have made gamma-secretase based therapy a formidable challenge. The combination of current understanding of the gamma-secretase biology with the recently failed clinical trial calls for the need to develop gamma-secretase inhibitors that specifically block A?42 production while leaving A?40 and other substrates intact. We have identified a series of compounds that exhibit these characteristics and they act through a distinct mechanism from that of A?42 gamma-secretase modulators. The overarching goal of this application is to elucidate the mechanism of action and therapeutic efficacy of A?42-specific gamma-secretase inhibition using an integrated approach of chemical biology, cell biology and animal models. We will develop a series of photoactivatable analogs to probe the molecular mechanisms of different mode of A?42 inhibition. We will determine their specificity and compare these with other classes of gamma-secretase inhibitors using novel cellular assays and in mice. Lastly, we will test the efficacy of A?42 specific inhibition on synaptic function and cognition in an AD knock-in mouse model. Overall, this proposal uses innovative approaches and model systems to address a topic highly significant in AD pathogenesis and therapeutic development.
Overwhelming evidence support a critical role of A?42 in AD pathogenesis. Accordingly, inhibition of gamma-secretase for A?42 production has emerged as an appealing therapeutic strategy for AD. This proposal directly addresses the mechanisms and functional role of A?42-specific inhibition in synaptic plasticity and learning and memory. It will greatly facilitate the understanding and development of ?-secretase-based AD therapy.
|Lian, Hong; Yang, Li; Cole, Allysa et al. (2015) NF?B-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron 85:101-15|
|Li, Hongmei; Guo, Qinxi; Inoue, Taeko et al. (2014) Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow. Mol Neurodegener 9:28|
|Gertsik, Natalya; Ballard, T Eric; Am Ende, Christopher W et al. (2014) Development of CBAP-BPyne, a probe for ?-secretase and presenilinase. Medchemcomm 5:338-341|
|Polito, Vinicia A; Li, Hongmei; Martini-Stoica, Heidi et al. (2014) Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med 6:1142-60|
|Crump, Christina J; Johnson, Douglas S; Li, Yue-Ming (2013) Development and mechanism of ýý-secretase modulators for Alzheimer's disease. Biochemistry 52:3197-216|
|Pozdnyakov, Nikolay; Murrey, Heather E; Crump, Christina J et al. (2013) ýý-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin. J Biol Chem 288:9710-20|
|Crump, Christina J; am Ende, Christopher W; Ballard, T Eric et al. (2012) Development of clickable active site-directed photoaffinity probes for ?-secretase. Bioorg Med Chem Lett 22:2997-3000|
|Guo, Qinxi; Li, Hongmei; Gaddam, Samson S K et al. (2012) Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives. J Biol Chem 287:2437-45|
|Crump, Christina J; Fish, Benjamin A; Castro, Suita V et al. (2011) Piperidine acetic acid based ?-secretase modulators directly bind to Presenilin-1. ACS Chem Neurosci 2:705-710|