Author ORCID Identifier

0000-0002-6373-1535

Date of Graduation

8-2018

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Louise McCullough, MD, PhD

Committee Member

Jarek Aronowski, MD, PhD

Committee Member

Andrew Bean, PhD

Committee Member

Shane Cunha, PhD

Committee Member

Ruth Heidelberger, MD, PhD

Committee Member

Claudio Soto, PhD

Abstract

In healthy brain tissue, toxic amyloid-β (Aβ) proteins are transported by the pulsatile flow of cerebrospinal fluid (CSF) along perivascular drainage pathways. Ischemic stroke may disrupt this process, leading to a perivascular build-up of Aβ, termed cerebral amyloid angiopathy (CAA). I hypothesize that an abnormal pattern of extracellular matrix deposition within the vascular basement membrane, termed fibrosis, impairs Aβ drainage from the aged brain after stroke. I further hypothesize that inhibition of astrocytic transforming growth factor-β (TGF-β) signaling can reverse these phenotypes. Finally, I also hypothesize that serum biomarkers of perivascular fibrosis can be used to diagnose CAA following intracerebral hemorrhage (ICH). To test these hypotheses, I first performed experimental stroke in young and aged wild-type mice, then measured basement membrane fibrosis and CSF flow using a variety of biochemical and physiological techniques. I also evaluated the contribution of astrocytes to these phenotypes using a primary cell culture model. Then, I treated aged mice with a TGF-β antagonist, and measured the impact on fibrosis and CSF flow. Finally, I explored the relevance of these findings to humans by measuring serum biomarkers of fibrosis after ICH, and correlating them to CAA etiology, injury severity and functional outcomes. Overall, my findings support a role for fibrosis in impairing perivascular Aβ drainage after stroke, which could lead to CAA and progressive cognitive decline in stroke survivors.

Keywords

Stroke, Fibronectin, Integrin, Amyloid, CAA, Glymphatic, CSF, TGF-beta, Astrocytes, Neurodegeneration

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