Alzheimer disease (AD), the most common form of dementia, is characterized by the extracellular deposition of parenchymal and vascular -amyloid (A), intracellular accumulation of tau as neurofibrillary tangles (NFTs), neuronal cell loss, and significant inflammation1,2. During the past decades, a major focus of research has been the understanding of the connection between parenchymal A, NFT, and neurodegeneration, with the contribution of vascular pathology to NFT and neurodegeneration remaining under studied. Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of A and has a close molecular relationship with AD. Unfortunately, there is no clear understanding of the molecular and cellular mechanisms and targets that underlie the contribution of CAA to neurodegeneration and dementia. Therefore, the main goal of this proposal is to dissect the mechanism(s) by which CAA leads to neuroinflammation, abnormal tau accumulation, and neurodegeneration. CAA has been associated to an active immune response and perivascular deposition of hyperphosphorylated tau; yet these three pathological entities have never been linked in a spatio-temporal context in relation to cognitive decline. Hence, we propose to determine if a disease- associated form of tau, catalyzed by a pro-inflammatory response, plays a major role on behavioral deficit and the synaptotoxicity observed in dementias associated to CAA, using a well-established genetic mouse model for CAA (Tg-FDD)12. We will also determine if the triggering receptor expressed on myeloid cells 2 (TREM2) plays a preponderant role in vascular amyloid deposition and vascular integrity in vivo during CAA progression. Furthermore, we will identify the potential role of tau on CAA and subsequent neurotoxicity by determining if the ablation of functional endogenous tau suppresses behavioral deficit and toxicity in our genetic mouse model for CAA. The proposed studies will provide a platform for the understanding of the role of CAA in neurodegeneration. Information gained from these studies might lead to the development of effective therapeutics not only for CAA and AD, but also for a number of neurodegenerative diseases characterized by the vascular accumulation of amyloid peptides.

Public Health Relevance

Cerebral amyloid angiopathy (CAA), a common finding in over 90% of Alzheimer's disease (AD) cases, is characterized by the deposition of amyloid in the cerebrovascular compartment. This overlap between AD and vascular brain pathology in dementia has been difficult to separate, with AD and vascular dementia probably existing as a continuum of distinct but mechanistically related processes. The studies outlined in this proposal will allow us to dissect in detail the mechanism(s) by which CAA leads to cognitive decline and may identify novel therapeutic targets for CAA and AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Mackiewicz, Miroslaw
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Indiana University-Purdue University at Indianapolis
Anatomy/Cell Biology
Schools of Medicine
United States
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