The neuroprotective roles for amyloid precursor protein (APR) and its soluble secreted fragment (sAPPa), a normal a-secretase cleavage product, have been demonstrated in culture systems against a broad spectrum of neuronal insults. Several protective roles observed in certain transgenic (Tg) mouse models overexpressing APP have also been inferred to sAPPa. The mechanisms underlying these actions, are however, scarcely studied. The objectives of this application are thus to investigate the molecular mechanisms of sAPPa's functions and to evaluate its beneficial effects on alleviating neuropathologies in mouse AD models. In preliminary studies, we demonstrated that mice or cells lacking APP are associated with increased stress kinase CDK5 activity and elevated tau phosphorylation, which can be restored by exogenous sAPPa. sAPPa possesses strong anti-apoptotic activity in NMDA-induced neuronal death which synergizes with IGF via a pathway involving Bcl-2. Importantly, we found neurogenic defect in young adult APP""""""""'"""""""" mice and identified a neurotrophic function of sAPPain various cell/tissue cultures, which is synergized by EGF. Chronic infusion of sAPPa into adult mice reveals that the neuronal progenitor cells in the subventricular zone contain major binding sites for sAPPa in vivo. sAPPa preferentially binds to the lipid-enriched microdomains on the cell surface. Taken together, we hypothesize that sAPPa plays broad neuroprotective roles in preventing neuronal degeneration and death, and more intriQuinalv, a crucialrole in neuropenesis at both the prenatal and postnatal stages. sAPPa treatment in CNS at a proper dosage and timing will improve neuropathologies developed in mouse AD models. We therefore propose in Aim 1 to assess the roles of sAPPa in reducing neuropathologies in Tau Tg mouse model. We will test whether sAPPa treatment can reduce tau-phosphorylation and NFT formation, provide excitoprotection, and prevent memory loss using tau mutant (R406W) transgenic mice.
Aim 2 will assess the potential roles of sAPPa in neurogenesis in APP""""""""'* and APP/APLP2 double knockout mice. We will examine whether neurogenesis levels in these mice associate with their mortality, and whether chronic infusion of sAPPa can stimulate proliferation of neuronal progenitor/stem cells in these mice and rescue neurogenesis impairment.
Aim 3 is to understand the molecular and cellular mechanism underlying the biological functions of sAPPa and to identify sAPPa-associated membrane protein(s). Molecular and cell biological approaches including crosslinking of membrane proteins with bound biotinylated sAPPa, lipid raft isolation, in combination with proteomic technologies, will be used to isolate and identify putative membrane-receptor(s) for sAPPa.. Our study will reveal novel physiological functions of APP/sAPPa as well as the underlying molecular mechanisms, and should shed light on potential therapeutic windows for sAPPa in the future.
|Chen, Yaomin; Wang, Bin; Liu, Dan et al. (2014) Hsp90 chaperone inhibitor 17-AAG attenuates A?-induced synaptic toxicity and memory impairment. J Neurosci 34:2464-70|
|Nakanishi, Nobuki; Ryan, Scott D; Zhang, Xiaofei et al. (2013) Synaptic protein ?1-takusan mitigates amyloid-?-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci 33:14170-83|
|Wang, Ruishan; Li, Jing Jing; Diao, Shiyong et al. (2013) Metabolic stress modulates Alzheimer's ?-secretase gene transcription via SIRT1-PPAR?-PGC-1 in neurons. Cell Metab 17:685-94|
|Zhang, Han; Zhang, Yun-wu; Chen, Yaomin et al. (2012) Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration. J Neurosci 32:15565-76|
|Kwak, Young-Don; Wang, Bin; Li, Jing Jing et al. (2012) Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration. J Neurosci 32:10971-81|
|Huang, Xiumei; Chen, Yaomin; Li, Wu-Bo et al. (2010) The Rps23rg gene family originated through retroposition of the ribosomal protein s23 mRNA and encodes proteins that decrease Alzheimer's beta-amyloid level and tau phosphorylation. Hum Mol Genet 19:3835-43|
|Kwak, Young-Don; Wang, Bin; Pan, Wei et al. (2010) Functional interaction of phosphatase and tensin homologue (PTEN) with the E3 ligase NEDD4-1 during neuronal response to zinc. J Biol Chem 285:9847-57|
|Liu, Yun; Zhang, Yun-Wu; Wang, Xin et al. (2009) Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1. J Biol Chem 284:12145-52|
|Ma, Tao; Zhao, YongBo; Kwak, Young-Don et al. (2009) Statin's excitoprotection is mediated by sAPP and the subsequent attenuation of calpain-induced truncation events, likely via rho-ROCK signaling. J Neurosci 29:11226-36|
|Zhang, Yun-wu; Liu, Shijie; Zhang, Xue et al. (2009) A functional mouse retroposed gene Rps23r1 reduces Alzheimer's beta-amyloid levels and tau phosphorylation. Neuron 64:328-40|
Showing the most recent 10 out of 14 publications