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Manipal Academy of Higher Education, India
Thesis Advisor: Robert Nagele, Ph.D.
Cell and Molecular Biology Program
Science Center, Room 290
Thursday, October 11, 2012
The pathogenesis of Alzheimer’s disease (AD) is still poorly understood. Recent epidemiological studies have identified diabetes mellitus (DM) and hypercholesterolemia (HC) as major risk factors for AD. The primary objective of my thesis was to investigate whether or not DM and HC increase the risk of AD initially through their deleterious effects on the brain vasculature which elicits blood-brain barrier (BBB) breakdown. This was investigated in DMHC pig model using quantitative immunohistochemistry (IHC). Results revealed focal regions of BBB breakdown and plasma influx into the brain as evidenced by detection of IgG in the brain interstitium as perivascular leak clouds and immuno-labeling of neuronal surfaces. This was accompanied by a corresponding increase in intraneuronal amyloid beta 1-42 peptide deposition, a hallmark of AD pathology. BBB breakdown and intraneuronal amyloid were reduced by treatment with Darapladib, a phospholipase-A2 inhibitor purported to curtail atherosclerosis by suppressing inflammation. Overall results suggest that conditions, like DMHC, are risk factors for AD because they can induce BBB breakdown, which disrupts brain homeostasis and initiates AD pathogenesis by triggering amyloid deposition. Additionally, the beneficial effects of Darapladib offer promise for therapies that target BBB compromise.
Chronic binding of autoantibodies to neurons made possible by BBB breakdown has been proposed as a driving force for intraneuronal amyloid deposition in AD brains. In view of this, the second objective of my dissertation was to identify the origin of brain-reactive autoantibodies (BAs). Using IHC, expression of peptidylarginine deiminases (PADs), a group of enzyme catalyzing protein citrullination (PC), were demonstrated in human cortex and hippocampus. PC is a post-translational deimination reaction that modifies protein structure potentially making it antigenic. PC has been linked with the production of disease-specific autoantibodies in several autoimmune disorders, including rheumatoid arthritis. Cortical and hippocampal neurons of AD and control brains showed selective and comparable expression of PAD4, whereas PAD2 expression was markedly elevated in cortical astrocytes of AD brains. These findings lead us to propose that in AD brain, the death of neurons and astrocytes containing citrullinated proteins causes the release of these proteins into the blood, which stimulates production of BAs.