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Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease
1Brown Medical School, Providence, RI, USA. Stephen_Salloway@brown.edu
Abstract:
APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimer's disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies, we have shown that the synaptic organizing protein agrin can be found in neurons, and is a major component of the brain microvascular basement membrane. Here, we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area (micro(2)) of prefrontal cortical microvessels. An average of 10 capillaries was measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9 micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimer's disease.
Insights
Individuals with two copies of the APOE4 gene (APOE4,4) show reduced capillary basement membrane area in Alzheimer's disease (AD) brains. This finding suggests a link between APOE4 genotype and microvascular changes in AD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Alzheimer's disease (AD) risk is linked to APOE4 homozygosity, but the underlying mechanism is unclear.
- Microvascular basement membrane injury is implicated in AD-related dementia.
- Agrin, a synaptic protein, is a key component of brain microvascular basement membranes.
Purpose of the Study:
- To compare the basement membrane surface area of cortical microvasculature in AD brains based on APOE genotype.
- To investigate the relationship between APOE4 status and microvascular integrity in AD.
Main Methods:
- Cortical microvasculature was stained with an anti-agrin antibody in 35 AD cases genotyped for APOE status.
- Quantitative morphometric analysis determined the mean capillary basement membrane area (CBMA).
- APOE3,3 and APOE4,4 homozygotes, and APOE3,4 heterozygotes were compared.
Main Results:
- APOE4,4 homozygotes exhibited significantly smaller CBMA (17.4 μm²) compared to APOE3,3 homozygotes (26.9 μm²).
- CBMA in APOE3,4 heterozygotes did not differ significantly from either homozygote group.
- Braak stage did not significantly affect CBMA, though a preliminary interaction with APOE4,4 and advanced Braak stages was noted.
Conclusions:
- APOE4,4 genotype is associated with a thinner microvascular basement membrane in the brains of Alzheimer's disease patients.
- These findings support a role for microvascular alterations in the pathogenesis of AD in APOE4 carriers.
- Further research with larger samples is needed to confirm the interaction between APOE4,4 and Braak stage.
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