Year of Publication

2018

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Molecular and Cellular Biochemistry

First Advisor

Dr. M. Paul Murphy

Abstract

Age-related neurologic disease is a significant and growing burden on our society. Although the largest share of research effort has typically been devoted to the common neurodegenerative illnesses (such as Alzheimer’s disease, or AD), the reality is that nearly all cases of neurodegenerative disease possess elements of mixed pathology. Vascular contributions to cognitive impairment and dementia (VCID) is a complex form of dementia, combining aspects of vascular disease and other forms of dementia, such as Alzheimer’s disease. This pathology is heterogeneous and can include cerebral amyloid angiopathy (CAA), hemorrhages, white matter infarcts, and changes to the neurovascular unit. Given the heterogeneous nature of VCID, we hypothesized that we could further elucidate mechanisms that drive dementia in VCID by examining pathology in mouse models and use this data to guide the study of human autopsy cases. Using a mouse model of VCID, we identified NHE1, a sodium hydrogen exchanger that was upregulated in these mice, as a possible candidate for a factor involved in cerebrovascular disease in humans. We saw a significant age effect of NHE1 in cases with Down syndrome (DS), leading us to further examine cerebrovascular pathology in individuals with DS. People with DS are at a high risk of developing cognitive impairment and dementia after the age of 50. In fact, virtually all adults with DS develop the neuropathology for an AD (beta-amyloid (Aß) senile plaques and tau neurofibrillary tangles) diagnosis by the age of 40 due to a triplication of chromosome 21. We found that these individuals develop CAA and microhemorrhages as a function of age, and that these rates are as severe as sporadic AD, despite an age difference of ~30 years. We also found that individuals with DS have different microglial morphologies than controls or individuals with AD. This data indicates that people with DS develop significant cerebrovascular and AD pathology, indicative of VCID. Overall, we found that mixed pathologies, specifically VCID, is an important contributor to the development of dementia and should be studied further to better understand how this pathology drives cognitive impairment. Further, it is clear that mouse models map imperfectly onto complex human diseases, and that significant work remains to be done towards achieving an adequate model of VCID.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2018.408

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