BACE1 is a type I transmembrane aspartyl protease which is essential for cleaving amyloid precursor protein (APP) at the -site. Only after this initial cleavage does - secretase further process the released APP C-terminal fragment to excise -amyloid peptide (A). While inhibiting BACE1 activity will reduce BACE1 processing of APP and will thus reduce the release of A, this inhibition will also lead to decrease cleavage of another BACE1 substrate, neuregulin-1 (Nrg1), and will reduce its signaling activity, which regulates various central nervous system functions such as myelination, synaptic plasticity and astrogenesis. We have demonstrated that genetic deletion of BACE1 causes hypomyelination, perhaps via reduced Nrg1 signaling. BACE1-null mice also exhibit schizophrenia-like behaviors, epileptic seizures and neurodegeneration, indicating that BACE1 plays a critical role in many brain functions. In this proposal, we will specifically investigate the contribution of Nrg1 signaling to the observed phenotypes because many of these neurological dysfunctions exhibited in BACE1-null mice are potentially related to alterations in the Nrg1/ErbB signaling pathway. We will test our central hypothesis that reduced BACE1-dependent Nrg1 signaling activity contributes to the observed multiple neurological dysfunctions in BACE1-null mice. Specifically, we will answer important questions as to whether elevated Nrg1 signaling activity will ameliorate or exacerbate BACE1-null phenotypes through examining BACE1-null mice engineered to express BACE1-cleaved Nrg1 N-terminal fragment and whether knock-in mice with disrupted cleavage in Nrg1 will produce phenotypes mimicking BACE1-null mice. Results from this study will not only resolve many ambiguous questions related to BACE1 and Nrg1 functions, but will also provide important guidance as to whether enhancing Nrg1 signaling activity will reverse or ameliorate potential side effects associated with long-term significant inhibition of BACE1 in AD patients.

Public Health Relevance

This proposal focuses on the study of two important molecules: BACE1 and neuregulin 1 (Nrg1). BACE1 is an enzyme required for generating -amyloid peptides (A), and excessive production of A is considered to cause Alzheimer's disease. Hence, inhibition of BACE1 is actively pursued as Alzheimer's prevention and therapy. BACE1 inhibitors will cause mechanism-based side effects has also not been systematically investigated. BACE1-null mice exhibit multiple neurological dysfunctions such as hypomyelination, schizophrenia-like behaviors, epileptic seizures and neurodegeneration, indicating that BACE1 plays a critical role in many brain functions. Nrg1 is a signaling molecule that regulates myelination, synaptic plasticity, neurogenesis and gliogenesis, etc., and is linked to the pathogenesis of schizophrenia. In BACE1-null mice, Nrg1 signaling activity appears reduced, and whether this reduction would be sufficient to cause or contribute to the neurological dysfunctions in BACE1-null mice will be investigated in this study. Results from this study will not only resolve many ambiguous questions related to Nrg1 function, but will also provide important guidance as whether enhancing Nrg1 signaling activity will reverse or ameliorate potential side effects associated with the long-lasting significant inhibition of BACE1 in AD patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS074256-04
Application #
8659521
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Shi, Qi; Ge, Yingying; Sharoar, Md Golam et al. (2014) Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. J Neurosci 34:13954-62
He, Wanxia; Hu, Jinxuan; Xia, Yuxing et al. (2014) ?-site amyloid precursor protein cleaving enzyme 1(BACE1) regulates Notch signaling by controlling the cleavage of Jagged 1 (Jag1) and Jagged 2 (Jag2) proteins. J Biol Chem 289:20630-7
Luo, Xiaoyang; He, Wanxia; Hu, Xiangyou et al. (2014) Reversible overexpression of bace1-cleaved neuregulin-1 N-terminal fragment induces schizophrenia-like phenotypes in mice. Biol Psychiatry 76:120-7
Yan, Riqiang; Vassar, Robert (2014) Targeting the ? secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 13:319-29
Hu, Xiangyou; He, Wanxia; Luo, Xiaoyang et al. (2013) BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep 4:40-9
Deng, Minzi; He, Wanxia; Tan, Ya et al. (2013) Increased expression of reticulon 3 in neurons leads to reduced axonal transport of * site amyloid precursor protein-cleaving enzyme 1. J Biol Chem 288:30236-45
Shi, Qi; Prior, Marguerite; Zhou, Xiangdong et al. (2013) Preventing formation of reticulon 3 immunoreactive dystrophic neurites improves cognitive function in mice. J Neurosci 33:3059-66
Hu, Xiangyou; Schlanger, Rita; He, Wanxia et al. (2013) Reversing hypomyelination in BACE1-null mice with Akt-DD overexpression. FASEB J 27:1868-73