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Characterization of cerebral vascular abnormalities in an Alzheimer’s disease mouse model

University of British Columbia

Alzheimer’s disease (AD) patients suffer progressive neurodegenerative loss of memory and other intellectual abilities leading to Dementia, the exact cause of this disease is still unknown. A central pathological hallmark of AD is the presence of an aggregated amyloid-beta peptide (abeta). A strong link between brain vascularity dysfunction and AD exits due to evidence of reduced blood-brain barrier (BBB) integrity preceding other AD neuropatholgies. Furthermore, BBB dysfunction could influence cerebral blood flow, which could in turn influence blood clotting mechanisms during AD. Current dogma holds that AD BBB leakiness is likely due to vascular deterioration and apoptosis. I propose an alternative hypothesis: angiogenesis and hypervascularization underlie increased vascular permeability in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice by examining the expression of tight junction (TJ) proteins (occludin and ZO-1) with markers of apoptosis and angiogenesis. In aged AD mice, a significant increase in the incidence of disrupted TJs was directly linked to an increased microvascular density, but not apoptosis, which strongly supports hypervascularity as a basis for BBB dysfunction. My results demonstrate that AD related BBB disruption is due to neoangiogenesis, resulting in the redistribution of TJs that maintain the barrier thus providing a new paradigm for connecting vascular remodelling with AD. Unique atypical nonvascular TJ expression was also noted in the aged Tg2576 mice including “halos” of ZO-1 expression surrounding dense-core abeta plaques and occludin expression on a subset of astrocytes sometimes associated with plaques. The observed brain TJ-related pathologies appeared to be linked to the presence of abeta. This argument was iii strengthened by observations of Tg2576 mice treated with abeta immunotherapy, which showed reduced brain abeta levels. Tg2576 mice actively immunized with abeta had normal BBB TJ morphology, no apparent occlusions, normal angiogenesis and lacked the unique atypical nonvascular TJ expression. An examination of the general status of the clotting abilities of the Tg2576 mouse was examined. Whole blood from aged Tg2576 mice clotted faster than controls. However, the biochemical components of the clotting cascades were normal, suggesting potential platelet involvement. Taken together, the observed BBB abnormalities will provide new entry points for therapeutic intervention.

Text

2011-04-07

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/33378

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/