LAUSR

ABSTRACT Pericytes are a major component of cerebrovasculature playing a key role in maintaining cerebrovascular homeostasis. These cells have also been suggested to regulate brain metabolism of amyloid‐&bgr; (A&bgr;), disturbances of which are believed to contribute to the pathogenesis of Alzheimer's disease (AD). To examine the effects of pericytes on brain A&bgr; metabolism, C3H/10T1/2 mouse mesenchymal stem cells were differentiated into pericytes and stereotaxically injected into the brains of amyloid AD model APP/PS1 mice at the age of 18 to 20 months. Consistent with a role of pericytes in modulating cerebrovascular function, brain microcirculation in the pericyte‐injected hemisphere of the mice was increased 3 weeks after implantation compared to the contralateral hemisphere when measured by laser speckle contrast analysis technology. Importantly, enzyme‐linked immunosorbent assay revealed that the levels of insoluble A&bgr;40 and A&bgr;42 were significantly lower in the hippocampus of the pericyte‐injected hemisphere of the APP/PS1 mice than that of the contralateral side. Consistently, immunohistochemical analysis demonstrated that the pericyte implantation reduced A&bgr; deposition in the hippocampus. When brain slices from the APP/PS1 mice were incubated with C3H/10T1/2 cell‐derived pericytes, A&bgr;42 levels were significantly reduced in a manner that depends on the expression of a major A&bgr; endocytic receptor, the low‐density lipoprotein receptor‐related protein 1 (LRP1). While LRP1 mediated the cellular uptake of A&bgr; in the pericytes, the amounts of major A&bgr;‐degrading enzymes were not affected by LRP1 knockdown. Together, our findings indicate that mesenchymal stem cell–derived pericytes have the capacity to reduce brain A&bgr; and related pathology, and suggest that cell‐based therapy through transplantation of pericytes may be a promising approach to prevent and/or treat AD.