Pericyte implantation in the brain enhances cerebral blood flow and reduces amyloid-β pathology in amyloid model mice

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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-β (Aβ), disturbances of which are believed to contribute to the pathogenesis of Alzheimer's disease (AD). To examine the effects of pericytes on brain Aβ 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 Aβ40 and Aβ42 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 Aβ deposition in the hippocampus. When brain slices from the APP/PS1 mice were incubated with C3H/10T1/2 cell-derived pericytes, Aβ42 levels were significantly reduced in a manner that depends on the expression of a major Aβ endocytic receptor, the low-density lipoprotein receptor-related protein 1 (LRP1). While LRP1 mediated the cellular uptake of Aβ in the pericytes, the amounts of major Aβ-degrading enzymes were not affected by LRP1 knockdown. Together, our findings indicate that mesenchymal stem cell–derived pericytes have the capacity to reduce brain Aβ and related pathology, and suggest that cell-based therapy through transplantation of pericytes may be a promising approach to prevent and/or treat AD.

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