135 - Interrogating the Relationship Between Vascular Stress and Microglial Activation in the APP/PS1 Transgenic Rat Model of Alzheimer’s Disease

Poster Board Number: 135
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Abstract Body : Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disease, affecting memory, cognition, personality, and behaviour. Nearly 1 million Canadians are currently living with AD or other dementias. Advanced age is the greatest risk factor for AD and since we have an aging population, this number is projected to double by 2031. It is widely accepted that extracellular β-Amyloid plaques and neurofibrillary tangles are pathological hallmarks of AD. However, over 40% of people aged 80 to 89 have these deposits but do not experience cognitive impairment. Furthermore, therapeutics targeting such mechanisms have yet to show favourable results in clinical practice, suggesting that other processes are responsible for the pathogenesis of AD. Dysregulated microglia have been shown in our lab to trigger neuroinflammation, neurodegeneration, and cognitive decline. Chronic microglial activation, particularly in white matter regions, is associated with loss of blood brain barrier (BBB) integrity and aberrantly low cerebral blood flow, increasing vulnerability to vascular stress. Vascular risk factors, as early as midlife, are linked to cognitive impairment and AD. It is unclear whether there is a direct relationship between vascular stress and chronic microglial activation in AD.
Objective/Hypothesis: The objective of this study was to investigate components of vascular stress, such as endothelial dysfunction and oxidative stress, using histological markers. We hypothesized that vascular stress is positively associated with microglial activation in AD.
Methods: Male and female Fisher 344 wildtype (n=4) and APP/PS1 transgenic rats (n=4) at 3, 9, and 15 months of age were used. Transgenic rats overexpressed human APP transgene with Swedish and Indiana mutations as well as human PS1 transgene with L166P mutation, representing a transgenic rat model of AD. Anatomical regions of interest, corpus callosum and hippocampus, were analyzed at the coronal sections of Bregma + 2.04 and – 3.00 mm. Immunohistochemistry was done to identify endothelial dysfunction, oxidative stress, and microglial activation using VCAM-1, Nox2, and OX6 primary IgG antibodies. Two-way ANOVA followed by Tukey’s post-hoc tests were conducted and p ≤ 0.05 was considered significant.
Results: Our results did not show significant differences of endothelial dysfunction or oxidative stress when quantifying VCAM-1 and Nox2 positive vessels in APP/PS1 rats compared to wildtype rats (p > 0.05). Additionally, we did not observe a positive associative relationship between vascular stress and microglial activation, as there was no evidence of increased microglial activation surrounding inflamed vessels. However, novel findings of unique age-dependent increases of non-specific IgG staining were observed in white matter regions and surrounding the ventricles.
Discussion: We hope to further investigate increased non-specific IgG staining surrounding the ventricles and its relationship with microglial activation, as IgG circulates in the blood and is not usually found in cerebrospinal fluid. Increased BBB permeability, decreased cerebral blood flow and impaired clearance of waste may elucidate this poorly understood finding which occurs in aging, AD, and other neurodegenerative diseases. Further exploration of the sophisticated correlates of AD is necessary in ameliorating early diagnosis and successful therapies, so those living with the disease can have better quality of life.