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LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4
Hiroshi Oue1, Yu Yamazaki1, Wenhui Qiao1
1Department of Neuroscience.
Insights
Vascular mural cell LRP1 deficiency impairs spatial memory in APOE4 mice, highlighting its role in brain health. This suggests LRP1
Area of Science:
- Neuroscience
- Vascular Biology
- Genetics
Background:
- Cerebrovascular dysregulation contributes to vascular cognitive impairment and dementia (VCID), a common aging-related condition.
- APOE4 genotype is a significant risk factor for both VCID and Alzheimer's disease (AD).
- Low-density lipoprotein receptor-related protein 1 (LRP1), an apoE receptor, is crucial in vascular mural cells.
Purpose of the Study:
- To investigate the impact of vascular mural cell-specific LRP1 deficiency on cerebrovasculature and cognitive function.
- To examine these effects in the context of human APOE3 and APOE4 genotypes.
Main Methods:
- Generation of vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) on human APOE3 and APOE4 backgrounds.
- Assessment of cognitive performance, specifically spatial memory, in aged mice.
- Analysis of cerebrovascular integrity, including glial activation, collagen IV levels, and blood-brain barrier (BBB) integrity.
Main Results:
- APOE4 smLrp1-/- mice exhibited impaired spatial memory compared to controls.
- APOE3 smLrp1-/- mice did not show significant memory deficits.
- APOE4 smLrp1-/- mice displayed increased paravascular glial activation, reduced cerebrovascular collagen IV, and disrupted BBB integrity.
Conclusions:
- Vascular mural cell LRP1 plays a critical role in maintaining cerebrovasculature integrity and function.
- The effect of LRP1 deficiency on brain health is dependent on the APOE genotype.
- Targeting LRP1 in vascular mural cells may offer therapeutic strategies for APOE4-associated cognitive decline.
Abstract:
Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.
