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CLEARANCE OF CAPILLARY OCCLUSIONS IMPROVES CORTICAL BLOOD FLOW AND COGNITIVE FUNCTION IN ALZHEIMER'S MOUSE MODELS

Author
Cruz Hernández, Jean Carlos
Abstract
Alzheimer disease (AD) is characterized by a loss of cognitive function caused by the dysfunction and death of neurons and other cells in the brain. This cell injury is largely due to the toxic effects of aggregates of amyloid-beta (Aβ), which accumulates into dense plaques in the brain. Research in humans and in animals suggests that brain blood flow is reduced in AD by ~30%. Although it likely contributes to cognitive impairment and disease progression, no physiological explanation for this hypoperfusion has emerged.
In part, studies of cerebral blood flow pathology have been limited by the inability to perform in vivo imaging of vascular function at cellular resolution. The focus of this thesis is to present the underlying cellular mechanism responsible for this hypoperfusion phenomena and Aβ clearance in AD mouse models. Chronic cranial windows and in vivo two-photon excited fluorescence microscopy were used to study cerebrovascular blood flow.
While no blood flow disruption in cortical arterioles or venules were observed, blood flow was found to be stalled in an average of 1.8% of cortical capillaries in mouse models of AD, as compared to 0.25% in wild type controls. These capillary stalls appeared early in disease progression, before any amyloid deposition. We found that the majority of the occlusions were caused by leukocytes, which adhered tightly to the endothelium. Indeed, blocking neutrophil adhesion in AD mouse models led to the fraction of capillary stalls decrease by 70 %, causing brain blood flow to increase by ~30% and cognitive function to improve.
These data suggest a working model to explain the origin of hypoperfusion in AD: Aβ accumulation leads to increased production of ROS that stresses endothelial cells and leads to increases in inflammatory receptors on the vessel lumen. This vascular inflammation causes leukocytes to adhere and plug capillaries, resulting in decreases in perfusion. This blood flow deficit could contribute to dementia independently of the direct effects of Aβ and could also accelerate Aβ aggregation by decreasing clearance of Aβ monomers.
This research provides for the first time an explanation for the long known phenomenon of reduced blood flow in Alzheimer’s disease, one which has an early and significant impact on the development of pathological phenotypes. Brief reviews of multi-photon microscopy (MPM) and Brain blood flow in AD are also presented
Date Issued
2017-08-30Subject
Alzheimer's disease; Biomedical engineering; Blood Flow; neutrophils; two-photon; Neurosciences
Committee Chair
Schaffer, Chris
Committee Member
Bass, Andrew Howard; Xu, Chunhui
Degree Discipline
Biomedical Engineering
Degree Name
Ph. D., Biomedical Engineering
Degree Level
Doctor of Philosophy
Type
dissertation or thesis