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Alzheimer's Disease Research - Philip Wong, Ph.D.

Alzheimer's Disease: Mechanism and Experimental Therapeutics

Dr. Wong, via a Program Project grant from the NIH, will examine the physiological roles of BACE 1, BACE2, and components of the γ-secretase and will conduct a critical evaluation of these proteins as therapeutic targets in efforts to ameliorate Αβ amyloidosis in AD.

PROJECT 1 - BACE1 and BACE2 in cognition and models of Aβ amyloidosis
In efforts to further clarify the physiological role of BACE1, we recognize that in addition to APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1), a ligand for members of the ErbB family of receptor tyrosine kinases. This signaling pathway is implicated in numerous roles in CNS development and functions, including myelination of central and peripheral axons. Interestingly, NRG1 is one of the first genes that has been linked to an increased risk of schizophrenia. Recent in vivo and in vitro studies indicate that NRG1/ErbB4 signaling plays a key role in structural and functional plasticity of glutamatergic synapses and regulates GABAergic transmission. Both, glutamate and GABA systems are thought to be of pathophysiological relevance in psychiatric diseases, particularly in schizophrenia.
Given the strong genetic and functional links of NRG1 to schizophrenia and roles for BACE1 in the biology of NRG1, the observation that NRG1 processing is altered in BACE1 knockout mice raises the possibility that perturbations in NRG1 signaling in these mice may result in the behavioral phenotypes reminiscent of some of the features of schizophrenia. In Project 1, we are focusing efforts to examine whether BACE1 knockout mice show evidence of sensorimotor-gating deficiency, behavioral signs of glutamatergic hypofunction and other typical endophenotypes of schizophrenia.

Project 2 - Nicastrin: physiological role and therapeutic target validation
Previous studies of PS1 transgene rescued-PS1 null mice indicated that PS1/g-secretase functions as a tumor suppressor in epithelia. To explain the tumorigenesis occurring in this mouse model, it was proposed that PS1 suppresses the β-catenin signaling pathway through interactions with the large hydrophilic loop domain of PS1, such that the lack of PS1 in the skin results in increased stability of β-catenin. However, contrary to this idea is the finding that mice with a homozygous deletion of exon 10 encoding part of the hydrophilic loop domain of PS1 (a mutation that effectively abolished interactions between PS1 and β-catenin but retains Υ-secretase activity) do not exhibit overt abnormalities, such as spontaneous skin cancers. Because deletion of PS1 leads to reduction of Υ-secretase activity, other pathways directly regulated by Υ-secretase are likely to participate in the tumorigenesis of Υ-secretase-deficient mice. One likely downstream pathway regulated by Υ-secretase that may participate in the tumorigenesis of epithelia is Notch, a well known developmental signaling pathway critical for binary cell fate determination involving differentiation, proliferation, and survival. Supporting this notion are two recent reports showing that Notch serves as a tumor suppressor in the skin. However, it remains to be determined whether the Notch pathway is solely responsible for tumorigenesis in mice with reduced Υ-secretase activity because considerable pathological differences exist between mice with reduced Υ-secretase activity and Notch1 conditional knock-out mice.
To clarify the mechanism whereby reduction of Υ-secretase leads to increased risk of squamous cell carcinoma (SCC), our studies in Project 2 focus on mice with genetic reduction of Υ-secretase, including animals with deletion of one allele of Nct (Nct+/- mice).