Administrations of human adult ischemia-tolerant mesenchymal stem cells and factors reduce amyloid beta pathology in a mouse model of Alzheimer's disease

Autor: Nicolas Duthilleul, Fabien Jammes, Taoufiq Harach, Yelizaveta A. Lukasheva, Theo Lasser, David Cheatham, Charles Muller, Tristan Bolmont, Valentin Zufferey, Victoria Cheatham
Rok vydání: 2017
Předmět:
0301 basic medicine
Genetically modified mouse
Aging
Pathology
medicine.medical_specialty
Amyloid beta
Human adult ischemia-tolerant mesenchymal stem cells
Hippocampus
Mice
Transgenic
Intravenous delivery
Mesenchymal Stem Cell Transplantation
03 medical and health sciences
0302 clinical medicine
Alzheimer Disease
Cell Movement
medicine
Transgenic mice
Animals
Humans
Molecular Targeted Therapy
Cells
Cultured
Neuroinflammation
Stem cell factors
Amyloid beta-Peptides
biology
business.industry
General Neuroscience
Amyloidosis
Mesenchymal stem cell
Brain
Alzheimer's disease
equipment and supplies
medicine.disease
Intranasal application
Disease Models
Animal
030104 developmental biology
Cerebral Abeta amyloidosis
Injections
Intravenous
biology.protein
Cytokines
Neurology (clinical)
Cerebral amyloid angiopathy
Inflammation Mediators
Geriatrics and Gerontology
Stem cell
business
030217 neurology & neurosurgery
Developmental Biology
Zdroj: Neurobiology of Aging. 51:83-96
ISSN: 0197-4580
Popis: The impact of human adult ischemia-tolerant mesenchymal stem cells (hMSCs) and factors (stem cell factors) on cerebral amyloid beta (Aβ) pathology was investigated in a mouse model of Alzheimer's disease (AD). To this end, hMSCs were administered intravenously to APPPS1 transgenic mice that normally develop cerebral Aβ. Quantitative reverse transcriptase polymerase chain reaction biodistribution revealed that intravenously delivered hMSCs were readily detected in APPPS1 brains 1 hour following administration, and dropped to negligible levels after 1 week. Notably, intravenously injected hMSCs 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 1 week, although increasing several Aβ-degrading enzymes and modulating a panel of cerebral cytokines, suggesting an amyloid-degrading and anti-inflammatory impact of hMSCs. Furthermore, 10 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 hMSCs in culture, in the absence of intravenous hMSC injection, was also sufficient to diminish cerebral amyloidosis in the mice. In conclusion, this preclinical 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.
Databáze: OpenAIRE
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