Despite significant advances made toward our understanding of the pathogenesis of Alzheimer's disease (AD), effective mechanism-based therapies are lacking as only symptomatic treatments for this devastating illness are currently available. Strong experimental support of the """"""""amyloid cascade hypothesis"""""""" has led to intense efforts aimed at decreasing the generation of A? peptides (especially A?42) or increasing their clearance as potential therapeutic strategies for the treatment of AD. Since A? peptides are generated through sequential processing of the ?-amyloid precursor protein (APP) by ?-secretase and ?-secretase, these two enzymes represent high priority targets for drug discoveries in efforts to attenuate A? amyloidosis in AD. The discovery of BACE1 as the ?-secretase stimulated intense drug discovery research programs to identify pharmacological inhibitors of the enzyme. While significant advances in experimental validation of BACE1 as an attractive therapeutic target for AD has been made, the identification of critical BACE1- associated signaling pathways linked to myelination, cognition and psychotic functions raise concerns regarding the potential mechanism-based toxicities associated with pharmacological inhibition of this aspartyl protease. Therefore, further evaluation of the physiological roles of BACE1, particularly its impact during aging should be of great value towards the development of safe and effective treatment for AD. We plan to address the issue of potential mechanism-based toxicities associated with decrease in BACE1 activity. We will first define the potential liabilities of reducing level of BACE1 in the nervous system on 1) myelination, 2) cognition and 3) psychotic/emotional alterations and to test the hypothesis that moderate reduction of BACE1 limits the potential mechanism-based toxicity associated with reduction of BACE1 (Specific Aim 1). Secondly, taking advantage of neuronal cultures derived from BACE1 null mice, we plan to study the regulation of BACE1- dependent NGR1-ErbB4 signaling and its effects on synaptic function (Specific Aim 2). Because it is not known whether hypomyelination and psychotic symptoms observed in BACE1 null mice are due to the lack of BACE1 during development, we plan in to test the hypothesis that deletion of BACE1 in adulthood and during aging does not lead to abnormal phenotypes, including hypomyelination and psychotic symptoms, using our conditional BACE1 transgenic mouse model to down regulate BACE1 during aging (Specific Aim 3). These proposed studies will critically evaluate the potential mechanism-based side effects associated with pharmacological inhibition of BACE1 aimed at amelioration of A? amyloidosis and have important implications for design of anti-BACE1 therapy for AD.

Public Health Relevance

Significant advances in identification of drug targets for Alzheimer's disease (AD) therapy have been made over the past several years, including the discovery of BACE1 as the 2-secretase involved in AD and the subsequent validation of this enzyme as an attractive therapeutic target for this devastating disease of the elderly. Because of the important roles that BACE1 play in the brain, it is plausible that pharmacological inhibition of BACE1 is associated with untoward side effects. Therefore, we will take advantage of our series of genetically altered BACE1 mouse models to critically evaluate the neurobiology of BACE1, particularly its impact during aging, in efforts towards the development of a safe and effective treatment for AD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Corriveau, Roderick A
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Johns Hopkins University
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Tsao, William; Jeong, Yun Ha; Lin, Sophie et al. (2012) Rodent models of TDP-43: recent advances. Brain Res 1462:26-39
Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew et al. (2012) Alzheimer's therapeutics: translation of preclinical science to clinical drug development. Neuropsychopharmacology 37:261-77
Chow, Vivian W; Savonenko, Alena V; Melnikova, Tatiana et al. (2010) Modeling an anti-amyloid combination therapy for Alzheimer's disease. Sci Transl Med 2:13ra1
Chiang, Po-Min; Ling, Jonathan; Jeong, Yun Ha et al. (2010) Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci U S A 107:16320-4
Shan, Xiu; Chiang, Po-Min; Price, Donald L et al. (2010) Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci U S A 107:16325-30
Savonenko, A V; Melnikova, T; Laird, F M et al. (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci U S A 105:5585-90
Nishitomi, Kouhei; Sakaguchi, Gaku; Horikoshi, Yuko et al. (2006) BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J Neurochem 99:1555-63
Ma, Guojun; Li, Tong; Price, Donald L et al. (2005) APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J Neurosci 25:192-8
Lazarov, Orly; Morfini, Gerardo A; Lee, Edward B et al. (2005) Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J Neurosci 25:2386-95
Laird, Fiona M; Cai, Huaibin; Savonenko, Alena V et al. (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25:11693-709

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