Role Of A Receptor In Amyloid Beta Deposition On Brain Vessels

Takahisa Kanekiyo, MD, PhD
Washington University, School of Medicine (St. Louis, MO)

Mentors

Guojun Bu, PhD
Washington University (St. Louis, MO)
Year Awarded:
2009
Grant Duration:
April 1, 2009 to June 30, 2009
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2009632
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern
Takahisa Kanekiyo, MD, PhD

LRP1 In Amyloid Beta Metabolism And CAA

Summary

Mounting pathological studies from Alzheimer's disease patients have shown that amyloidbeta deposits are found not only in senile plaques but also in cerebral blood vessel as cerebral amyloid angiopathy (CAA), a major cause of intracranial hemorrhage and progressive dementia in elderly population. Amyloid beta deposition in CAA is detected primarily in the smooth muscle layer of cerebral arteries. The low-density lipoprotein receptor-related protein 1 (LRP1), known as amyloidbeta scavenger receptor, is abundantly expressed in smooth muscle cells. Therefore, the specific aims are designed to provide a comprehensive assessment of the function of LRP1 in amyloid beta metabolism and in CAA pathogenesis as well as the effect of amyloid beta on LRP1 expression and function in smooth muscle cells.

Details

The deposition of amyloid beta in brain blood vessels causes brain bleeding and progressive dementia in aged individuals. Because amyloid beta scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in brain vessels, we are focusing on the association of LRP1 with the amyloid beta deposition on brain vessel walls. The specific aims of this project are designed as follows; 1) Characterization of LRP1-mediated metabolism of amyloid beta in blood vessels, 2) Analyze the effects of the amyloidbeta on LRP1 expression and function, and 3) Define the role of LRP1 in amyloid deposition on brain blood vessels using animal models.

Research Updates

Mounting evidence from studies of Alzheimer's disease patients have shown that beta‐amyloid (Aβ) deposits are found not only in brain plaques but also in cerebral (brain) blood vessels as a condition called “cerebral amyloid angiopathy”— a major cause of brain bleeding and progressive dementia in aged individuals. Aβ deposits in cerebral blood vessels is detected primarily in the smooth muscle layer of cerebral arteries (one type of blood vessel). The Aβ scavenger receptor, called low‐density lipoprotein receptor‐related protein 1 (LRP1), is abundantly expressed in blood vessels. In this three month grant, Dr. Takahisa Kanekiyo and collaborators demonstrated that brain vascular smooth muscle cells took up Aβ and that LRP1 is abundantly expressed in brain vascular smooth muscle cells. When LRP1 was suppressed in these particular cells, the Aβ uptake and degradation were significantly decreased. This result clearly indicates the important roles of LRP1 in Aβ metabolism in the brain vascular smooth muscle cells.

P.I. relinquished his BrightFocus grant due to scientific overlap with an American Heart Association Fellowship award.

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