Administrations of Human Adult Ischemia-Tolerant Mesenchymal Stem Cells and Factors Reduce Amyloid-Beta Pathology in a Mouse Model of Alzheimer’s Disease – Neurobiology of Aging

The impact of human adult ischemia-tolerant mesenchymal stem cells (hMSC) and factors (SCF) on cerebral amyloid-beta (Aβ) pathology was investigated in a mouse model of Alzheimer’s disease (AD). To this end, hMSC were administered intravenously to APPPS1 transgenic mice that normally develop cerebral Aβ. Quantitative RT-PCR biodistribution revealed that intravenously-delivered hMSC were readily detected in APPPS1 brains one hour following administration, and dropped to negligible levels after 1 week. Notably, intravenously injected hMSC that migrated to the brain region were localized in the cerebrovasculature, but they also could be observed in the brain parenchyma particularly in the hippocampus, as revealed by immunohistochemistry. A single hMSC injection markedly reduced soluble cerebral Aβ levels in APPPS1 mice after one week, while increasing several Aβ-degrading enzymes and modulating a panel of cerebral cytokines, suggesting an amyloid-degrading and anti-inflammatory impact of hMSC. Furthermore, ten weeks of hMSC treatment significantly reduced cerebral Aβ plaques and neuroinflammation in APPPS1 mice, without increasing cerebral amyloid angiopathy or microhemorrhages. Notably, a repeated intranasal delivery of soluble factors secreted by hMSC in culture, in the absence of intravenous hMSC injection, was also sufficient to diminish cerebral amyloidosis in the mice. In conclusion, this pre-clinical study strongly underlines that cerebral amyloidosis is amenable to therapeutic intervention based on peripheral applications of hMSC or hMSC factors, paving the way for a novel therapy for Aβ amyloidosis and associated pathologies observed in AD.