The incidence of Alzheimer disease (AD) with vascular degeneration is greatly increased following cerebral hemorrhagic stroke in which cerebral amyloid angiopathy (CAA) occurs in affected brain areas. The most common form of CAA is of the amyloid beta-peptide (A?) type. A?, which is derived from the beta-amyloid precursor protein (APP) by sequential proteolytic cleavages from ?-secretase (BACE1) and ?-secretase, is widely believed to trigger a cascade of pathological events culminating in AD including accompanied by degeneration of vascular cells: vascular smooth muscle cells (VSMCs), vascular endothelial cells (VENCs) and pericytes. While extensive studies on pericytes in CAA have been performed, multiple studies demonstrated that an increasing accumulation of A? in the vessel basement membrane is associated with the degeneration of adjacent VSMCs and VENCs. Importantly, our recent preliminary data showed that cerebral vascular cells from human CAA brains express high levels of ?-secretase (BACE1). However, what causes vascular degeneration or death in CAA remains unclear. We recently reported that a cell death receptor, TNFRI, is required for A?- induced cell death and depletion of TNFRI reduced BACE1. In this application, we will study whether and how BACE1 can be up-regulated in vascular cells and what molecular mechanisms of BACE1 elevation causes cerebral vascular cell death in our new mouse models of AD related CAA. The ultimate goal of this proposal will not only advance our understanding the mechanisms of CAA- induced hemorrhage but, also to, in principle, identify novel therapeutic targets and offer novel alert for potential side effects of BACE1 inhibitors in patients with Alzheimer?s disease accompanying vascular degeneration. Key words: BACE1, TNF? inflammation, animal models, neurodegeneration

Public Health Relevance

The molecular roles of BACE1 in cerebral vascular degeneration in Alzheimer?s disease are not clear. In this application, we proposed, by using two new animal models, to study how cerebral amyloid angiopathy (CAA)/BACE1 enhances cerebral vascular degeneration, which contributes to Alzheimer?s disease. Completion of this project will help not only advance our understanding of normal physiological roles of BACE1 in cerebral vascular cells and pathological mechanisms of hemorrhage but, also will identify novel therapeutic targets and offer a novel alert of potential side effects of BACE1 inhibitors in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092610-03
Application #
9562141
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
2016-09-30
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Roskamp Institute, Inc.
Department
Type
DUNS #
968547583
City
Sarasota
State
FL
Country
United States
Zip Code
34243
Zhang, Zhengrong; Huang, Jing; Shen, Yong et al. (2017) BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia. Front Mol Neurosci 10:302
Zhang, Xinzhu; Yang, Jian; Li, Yuhong et al. (2017) Sex chromosome abnormalities and psychiatric diseases. Oncotarget 8:3969-3979
Shen, Yong; Wang, Haibo; Sun, Qiying et al. (2017) Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment. Biol Psychiatry :
Li, Cuicui; Zhou, Chenglin; Li, Rena (2016) Can Exercise Ameliorate Aromatase Inhibitor-Induced Cognitive Decline in Breast Cancer Patients? Mol Neurobiol 53:4238-4246
Shen, Yong; Li, Rena (2016) What do we know from clinical trials on exercise and Alzheimer's disease? J Sport Health Sci 5:397-399
Zhou, Yuehui; Zhao, Min; Zhou, Chenglin et al. (2016) Sex differences in drug addiction and response to exercise intervention: From human to animal studies. Front Neuroendocrinol 40:24-41
Li, Rena; Ma, Xin; Wang, Gang et al. (2016) Why sex differences in schizophrenia? J Transl Neurosci 1:37-42
Li, Rena (2016) Physical activity and prevention of Alzheimer's disease. J Sport Health Sci 5:381-382
Saleh, Huda; Saleh, Ayeh; Yao, Hailan et al. (2015) Mini review: linkage between ?-Synuclein protein and cognition. Transl Neurodegener 4:5