Alzheimer's disease (AD) is the leading cause of dementia, and there is a pressing need to develop treatments to mitigate its enormous human and public health impact. Amyloid-? (A?) is a key pathogenic factor in AD, but its mechanisms of action are not well understood. In addition to damaging neurons and glia, A? also impairs vital neurovascular mechanisms that regulate the cerebral blood supply, thus increasing the brain's susceptibility to hypoxic-ischemic injury. Vascular dysfunction may also compromise brain A? clearance, promoting the retention of the peptide and its damaging effects. During the previous funding period we have established that A? exerts its deleterious vascular effects by engaging the A?-binding scavenger receptor CD36. CD36, in turn, leads to the production of reactive oxygen species (ROS) by activating Nox2. However, the cells expressing CD36 on which brain A? acts on the abluminal side of cerebral blood vessels to increase Nox2-dependent ROS production remain unknown and their elucidation may suggest novel targets for AD therapy. Resident brain macrophages, mainly perivascular macrophages (PVM), reside along the A? clearance pathway, express CD36 and Nox2, and are in close contact with the outer vessel wall. Therefore, PVM are uniquely positioned to contribute to vascular oxidative stress and neurovascular dysfunction induced by brain A?. The central hypothesis of this application is that CD36 in PVM participates in the deleterious vascular effects of A? and in the long-term consequences of A? overproduction. We will test the following specific hypotheses: (1) PVM are the cells on which brain A? acts to induce vascular oxidative stress and dysfunction;(2) CD36 in PVM is responsible for these actions of A?, and (3) CD36 in PVM contributes to the long-term consequences of A? overproduction, including cognitive deficits and perivascular A? accumulation. Our studies will use state-of-the-art methods to investigate neurovascular regulation in mice. Pharmacological approaches and bone marrow chimeras will be used to investigate the specific role of CD36 in PVM in A?-induced oxidative stress, neurovascular dysfunction, and cognitive deficits.
There is an urgent need to develop treatments for Alzheimer's disease (AD), the most common cause of dementia. We propose to investigate how the A? peptide, a key pathogenic factor in AD, damages cerebral blood vessels and contributes to the brain dysfunction underlying the dementia. We will focus on the role of perivascular macrophages and on the scavenger receptor CD36. The proposed studies may establish CD36 on perivascular macrophages as a new therapeutic target to counter the deleterious vascular effects of A? on the brain.
|Gorelick, Philip B; Furie, Karen L; Iadecola, Costantino et al. (2017) Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association. Stroke 48:e284-e303|
|Yanagida, Keisuke; Liu, Catherine H; Faraco, Giuseppe et al. (2017) Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc Natl Acad Sci U S A 114:4531-4536|
|Murthy, Santosh B; Gupta, Ajay; Merkler, Alexander E et al. (2017) Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Stroke 48:1594-1600|
|Demuth, Hans-Ulrich; Dijkhuizen, Rick M; Farr, Tracy D et al. (2017) Recent progress in translational research on neurovascular and neurodegenerative disorders. Restor Neurol Neurosci 35:87-103|
|Iadecola, Costantino (2017) The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96:17-42|
|Park, Laibaik; Uekawa, Ken; Garcia-Bonilla, Lidia et al. (2017) Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer A? Peptides. Circ Res 121:258-269|
|Merkler, Alexander E; Gialdini, Gino; Yaghi, Shadi et al. (2017) Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale. Stroke 48:3073-3077|
|Faraco, Giuseppe; Park, Laibaik; Zhou, Ping et al. (2016) Hypertension enhances A?-induced neurovascular dysfunction, promotes ?-secretase activity, and leads to amyloidogenic processing of APP. J Cereb Blood Flow Metab 36:241-52|
|Iadecola, Costantino (2016) Vascular and Metabolic Factors in Alzheimer's Disease and Related Dementias: Introduction. Cell Mol Neurobiol 36:151-4|
|Koizumi, Kenzo; Wang, Gang; Park, Laibaik (2016) Endothelial Dysfunction and Amyloid-?-Induced Neurovascular Alterations. Cell Mol Neurobiol 36:155-65|
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