It is now known that most dementia patients have a combination of Alzheimer's pathology and Vascular Contributions to Cognitive Impairment and Dementia (VCID).1-4 This has led the NIH to prioritize studies examining vascular contributions to dementia, especially small vessel disease and its interplay with Alzheimer's. Cerebral Amyloid Angiopathy (CAA) is one of the most common small vessel diseases linked to dementia. It is found in almost all Alzheimer's patients (~90%) and many elderly (~30%),5-10 and is characterized by widespread deposition of amyloid-? (A?) within cerebral arterioles. Previously, we discovered NADPH oxidase-derived oxidative stress plays a causal role in CAA pathogenesis; and heparan sulfate proteoglycans (HSPG) are an initiator of A?-induced oxidative stress and cerebral vessel dysfunction. Our pilot studies extend upon these findings: 1) Global knockout of the Nox2 catalytic subunit of NADPH oxidase selectively and robustly reduces CAA and improves neurobehavior in APPPS1 mice; 2) Cerebral vessel levels of lipoprotein receptor-related protein 1 (LRP1) ? a transporter strongly linked to A? clearance at the blood brain barrier (BBB) ? are reduced in APPPS1 mice; and 3) Nox2 knockout reverses this change in LRP1 expression. Yet many knowledge gaps remain ? gaps that must be addressed to reach our long-term goal of developing an effective CAA-directed therapy. In the present grant, we address the following knowledge gaps: 1) Establishing that cerebral vessels (and not brain parenchyma) are the main source of oxidative stress driving CAA pathogenesis; 2) Identifying HSPG as a key initiator of vascular oxidative stress-induced CAA formation; 3) Determining NADPH oxidase is a primary driver of vascular oxidative stress-induced CAA formation; and 4) Establishing that disrupted LRP1- mediated A? clearance at the BBB is a mechanism by which vascular oxidative stress promotes CAA. We will test these gaps using the following methods: a) In vitro models of A?-induced oxidative stress and vascular dysfunction; b) In vivo models of CAA-induced vascular oxidative stress, cerebral vessel dysfunction, and neurobehavioral deficits; c) Time- and cell-specific knockout of EXT1 (the enzyme that synthesizes heparan sulfate chains on HSPG) and Nox2; e) Lentiviral transduction of Glypican-1 (the most highly expressed HSPG in CAA-laden vessels), Nox2, and LRP1; f) In vivo assessment of A? efflux, influx, and paravascular transport via fluorescent- and 125I-labeled A? imaging; and g) Histopathological assessments of HSPG, NADPH oxidase activity, oxidative stress, and CAA in cerebral vessels isolated from autopsied Alzheimer's and non-Alzheimer's patients. If successful, our studies will 1) Elucidate the molecular cascade by which A? and CAA induce vascular oxidative stress; 2) Establish that oxidative stress generated from cerebral vessels is a major contributor to CAA pathogenesis; and 3) Identify LRP1 as the downstream effector by which vascular oxidative stress promotes CAA. Through these studies, new therapeutic targets will likely be identified.

Public Health Relevance

Most dementia patients have co-existing Alzheimer's disease and Vascular Contributions to Cognitive Impairment and Dementia (VCID). Cerebral amyloid angiopathy (CAA) bridges these two pathologies given that it is found in the majority of Alzheimer's patients and is a proven risk factor for ischemic stroke, cerebral hemorrhage, and dementia. CAA is therefore a promising therapeutic target for dementia patients. In the present proposal, we plan to elucidate the upstream molecular events causing CAA-induced vascular oxidative stress and the downstream mechanisms by which vascular oxidative stress promotes CAA formation. If successful, new molecular targets for CAA-directed therapy will be discovered for dementia patients, which would be pursued in future translational studies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Multi-Year Funded Research Project Grant (RF1)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code