Microvascular Stress as a Pathway to Neurodegeneration in Alzheimer's

Project Abstract
Changes to cerebral microvasculature that impact blood flow and blood brain barrier function are increasingly
recognized as a key feature of early Alzheimer’s disease (AD) and cognitive impairment. The underlying
cause of this dysfunction is largely unknown, though data from transgenic mice indicates pathways related to
microvascular stress (inflammation, senescence, and angiogenesis) are upregulated with increasing amyloid
beta and tau deposition. This research will make use of human tissue samples collected in the Massachusetts
Alzheimer’s Disease Research Center (ADRC) and mouse models to examine the contribution of
microvascular stress to AD. In Aim 1, we will determine when and where microvascular stress appears in
relation to accumulation of amyloid beta plaques and tangles. In Aim 2, we will determine if microvascular
stress contributes to functional weakening of the blood brain barrier (BBB) in AD by measuring a panel of
serum proteins and by microdissecting “leaky” and “non-leaky” vessels to identify a mechanistic basis for
dysfunction at the level of individual vessel segments. In Aim 3 we will manipulate gene expression in
endothelial cells and test the causal role of specific microvascular stressors to pathological AD changes. This
work will assess human vascular transcriptomes from multiple brain regions in Alzheimer’s, providing
unparalleled information about how vascular cells are affected by AD pathology and insight into variability of
human brain vasculature that might underlie regional differences in disease susceptibility. Further, we will
make use of innovative methods including multiplex immunofluorescence to measure up to 18 proteins in
tissue sections at once, clear brain preparations to assess spatial relationships between stress markers and
AD pathology, and a novel adeno-associated virus that can specifically target endothelial cells in vasculature
and that may be an exciting tool for future therapeutic gene delivery. Overall, these studies will significantly
contribute to our knowledge of the biological mechanisms of impaired microvascular function in AD and will
help uncover biomarkers to identify patient populations that would benefit from vascular-directed therapeutics
arising from this project.

Grant Number: 5R01AG071567-04
NIH Institute/Center: NIH
Principal Investigator: Rachel Bennett