Alzheimer's disease (AD) is closely linked to cardiovascular risk factors. The renin-angiotensin system contributes to cardiovascular diseases through its bioactive peptide angiotensin II (AngII) acting on AT1 receptor. There is compelling evidence that AngII and AT1 receptor contribute to AD. The important role of AngII and AT1 receptor has also been enhanced by several ongoing clinical trials to determine effects of AT1 receptor antagonism on improving cognitive dysfunction and neuropathology of AD. The parent grant is studying the role of AngII infusion on mechanisms of thoracic aortic aneurysms. AngII infusion in mice shows impairment of memory and recognition, accompanied by higher gene expression involved in -amyloid generation and AD, although related neuropathology and potential mechanisms have not been determined. This Administrative Supplement will test a central hypothesis that AngII promotes cognitive decline correlated with region-specific changes in cerebral arteries that are augmented by vascular smooth muscle cell-specific deletion of LRP1. We will use our well- established AngII-infusion mouse model as well as a unique mouse model (smooth muscle cell- specific LRP1 -/-) described in the parent grant. Mice will be infused with AngII in both male and female mice to answer 4 questions that are within the scope of the parent grant: (1) Is AngII infusion induced cognitive decline dependent on blood pressure increase? (2) Is AngII- induced cognitive dysfunction influenced by hypercholesterolemia? (3) Does the AngII-induced cognitive decline correlate with region-specific changes in cerebral artery pathology? (4) Does deletion of LRP1 in smooth muscle cells augment the cognitive decline and cerebral vascular pathology during AngII infusion? The proposed project will be benefitted from (1) Water maze (the standard method for AD) to determine cognitive function in our Rodent Behavior Core, (2) sophisticated Light Microscopy Core on campus that permits detailed characterization of cerebral vascular structure in mice, and (3) our well-respected Alzheimer's Disease Center and collaboration with neurological scientists (Dr. Johnson at our institution and Dr. Holtzman at Washington University). We are confident that the experiments proposed in this Administrative Supplement will assimilate preliminary data to enable development of an R01 that will focus on providing new insights into understanding mechanisms of AD. The potential R01 application will also be strengthened by a spectrum of mouse models and pharmacological tools that have already been developed in the parent grant or other awards we received, and well-recognized AD mouse models in our Alzheimer's Disease Center and from Dr. Johnson.
| Au, Dianaly T; Ying, Zhekang; Hernández-Ochoa, Erick O et al. (2018) LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca2+ Signaling and Expression of Cytoskeleton-Related Proteins. Arterioscler Thromb Vasc Biol 38:2651-2664 |
| Wu, Chia-Hua; Mohammadmoradi, Shayan; Chen, Jeff Z et al. (2018) Renin-Angiotensin System and Cardiovascular Functions. Arterioscler Thromb Vasc Biol 38:e108-e116 |
| Sawada, Hisashi; Chen, Jeff Z; Wright, Bradley C et al. (2018) Heterogeneity of Aortic Smooth Muscle Cells: A Determinant for Regional Characteristics of Thoracic Aortic Aneurysms? J Transl Int Med 6:93-96 |
| Wu, Chia-Hua; Daugherty, Alan; Lu, Hong (2018) Multifaceted functions of macrophages in atherosclerosis. Curr Opin Lipidol 29:275-276 |
| Majesky, Mark W (2018) Vascular Development. Arterioscler Thromb Vasc Biol 38:e17-e24 |
| Berthiaume, Andrée-Anne; Hartmann, David A; Majesky, Mark W et al. (2018) Pericyte Structural Remodeling in Cerebrovascular Health and Homeostasis. Front Aging Neurosci 10:210 |
| Sawada, Hisashi; Rateri, Debra L; Moorleghen, Jessica J et al. (2017) Smooth Muscle Cells Derived From Second Heart Field and Cardiac Neural Crest Reside in Spatially Distinct Domains in the Media of the Ascending Aorta-Brief Report. Arterioscler Thromb Vasc Biol 37:1722-1726 |
| Daugherty, Alan; Chen, Zheying; Sawada, Hisashi et al. (2017) Transforming Growth Factor-? in Thoracic Aortic Aneurysms: Good, Bad, or Irrelevant? J Am Heart Assoc 6: |
| Wu, Congqing; Daugherty, Alan; Lu, Hong (2017) A Color Segmentation-Based Method to Quantify Atherosclerotic Lesion Compositions with Immunostaining. Methods Mol Biol 1614:21-30 |
| Lu, Hong; Daugherty, Alan (2017) Aortic Aneurysms. Arterioscler Thromb Vasc Biol 37:e59-e65 |
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