Effect of Vascular Function on Alzheimer’s Disease Public
Zhang, Xiancong (Spring 2018)
Abstract
Alzheimer’s disease (AD) is characterized by a state of reduced cerebral blood flow, which may partly be secondary to cerebral artery vascular dysfunction. Recent studies have shown that systemic vascular dysfunction may precede Alzheimer’s disease. We hypothesize that biochemical changes associated with AD progression can impact vascular function. We also hypothesize that AD transgenic rats progressively develop vascular dysfunction and cognitive decline, and can be mediated by candesartan. Homogenates were prepared from temporal lobe samples from patients with or without tauopathies.The chronic effects of brain homogenates on vascular function was characterized using isolated wild-type rat aorta segments incubated with homogenates for 24 hours. Rat aortas were isometrically mounted and the vascular function was assessed by examining contractile responses to KCl and phenylephrine, and relaxation responses to methacholine and sodium nitroprusside. The acute effect of homogenates on vascular function was measured using wild-type rat aorta segments after maximal relaxation by methacholine. AD transgenic and wild-type rats were administered with candesartan daily since 12-months-old. Blood pressures of AD transgenic and wild-type rats were measured using femoral artery catheterization at 12 months and 18 months and compared to controls. Vascular function of AD transgenic rats was studied at 12 months and 18 months with the same methodology.
Preliminary data from chronic studies suggests that, amyloid group patient tissues are less sensitive to methacholine-dependent relaxation compared to tissue from Tau and control groups. Preliminary data from acute studies suggests that tissue from the tau group results in more severe contractile effects on maximally relaxed aortas compared to amyloid and control groups. Results from 12-month blood pressure of AD transgenic rats show no difference before the progression of AD, comparing to the controls. Results from 12-month contractility study of AD transgenic rats show no significant difference in vessel functions.
These results are significant because they suggest that biochemical changes associated with AD can impact vascular function. Therefore, these studies suggest that there is an association between AD and vascular dysfunction and propose new therapeutic targets.
Table of Contents
INTRODUCTION 1
ALZHEIMER’S DISEASE 1
ALZHEIMER’S AS A NEURODEGENERATIVE DISEASE 2
ALZHEIMER’S AS A VASCULAR DISORDER 3
NITRIC OXIDE (NO) 5
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) 6
PURPOSE 7
MATERIAL AND METHODS 8
TRANSGENIC RAT 8
HOMOGENATE 8
KREBS BUFFER 9
POTASSIUM CHLORIDE (KCL) 9
PHENYLEPHRINE (PE) 10
METHACHOLINE (MCH) 10
SODIUM NITROPRUSSIDE (SNP) 11
CANDESARTAN 11
ASSESSING VASCULAR FUNCTION 12
Homogenate Chronic Study 12
Homogenate Acute Study 13
AD Transgenic Study 13
RESULTS 14
EFFECT OF CHRONIC BRAIN HOMOGENATE EXPOSURE ON VASCULAR FUNCTION 14
EFFECT OF ACUTE BRAIN HOMOGENATE EXPOSURE ON VASCULAR FUNCTION 15
VASCULAR FUNCTION IN AN AD TRANSGENIC MODEL 15
DISCUSSION 16
REFERENCES 22
FIGURES
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