Student Theses and Dissertations

Author

Anna Kruyer

Date of Award

2015

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Strickland Laboratory

Abstract

Numerous epidemiological studies link vascular disorders, such as hypertension, diabetes and stroke, with Alzheimer’s disease. Hypertension, specifically, is an important modifiable risk factor for late onset Alzheimer’s disease. Despite the abundance of clinical data connecting these conditions, animal studies investigating the connection between the two are lacking. To examine the link between midlife hypertension and the onset of Alzheimer’s disease later in life, chronic hypertension was induced in the TgSwDI mouse model of Alzheimer’s disease in early adulthood using long-term administration of the eNOS inhibitor, N ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). L-NAME treatment accelerated cognitive deficits, microvascular deposition of the amyloidbeta peptide, vascular inflammation, blood brain barrier leakage, and pericyte loss in these mice. Though lysosomal markers were increased in hypertensive TgSwDI mice relative to all other groups, autophagic structures appeared to be increased in both hypertensive TgSwDI mice, as well as hypertensive WT mice. The increased presence of these structures altered cellular morphology at the neurovascular unit and compromised the blood brain barrier in hypertensive mice. Additionally, midlife hypertension induced hippocampal neurodegeneration at an early age in TgSwDI mice. Neuronal loss is a defining characteristic of pathology in Alzheimer’s disease, but is not replicated in many mouse models of the disease. Therefore, this may be a useful research model of Alzheimer’s disease with mixed vascular and amyloid pathologies and may display classical features of the disease missing in more canonical mouse models.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Available for download on Sunday, June 04, 2017

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