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

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.