Thomas Dowlearn

Introduction:  Alzheimer’s Disease (AD) is a neurodegenerative disease that progressively impairs memory, thinking, and reasoning skills. It is the 6^th leading cause of death in the U.S. accounting for 60-80% of dementia cases, and its prevalence is projected to affect 74.7 million people globally by 2030.^1-3 AD is most often sporadic and affects people older than 65.^2-3 Although the exact pathogenesis of AD is still unknown, the degradation of the blood-brain barrier (BBB) is now suspected as an early factor.^4-5 Pericytes, a main component of the BBB, reduce in number and become dysfunctional in AD. These changes result in hypoperfusion of the brain parenchyma and the accumulation of toxic beta-amyloid proteins (Aβ) and other unwanted substances.⁶ These factors lead to the degradation of neural synapses, which eventually causes cognitive impairment.⁵ Currently no cure exists for AD, but various treatments are offered to temporarily improve symptoms.³ Cutting edge research is now investigating a cure for AD by restoring the function of the BBB.  Methods: In one study, mouse mesenchymal stem cells were differentiated into pericytes by culturing them with transforming growth factor-β (TGF– β). The pericytes were then transfected with green fluorescent protein (GFP) plasmid vector. Next, the pericytes were injected into the right hemisphere of amyloid AD model mice brains. Additionally, saline solution lacking pericytes was injected into the left hemisphere as a control. The location of the injection was held constant for each specimen. Cerebral microcirculation was visualized actual time with laser speckle contrast analysis (LASCA) technology. Aβ40 and Aβ42 levels were measured using Aβ enzyme-linked immunosorbent assay (ELISA) on supernatant from centrifuged hippocampal samples. Finally, hippocampal sections were resected, frozen, and incubated with anti-GFP antibody, anti-platelet-derived growth factor receptor β (PDGFR β) antibody, anti-collagen IV antibody, and anti-pan Aβ antibody. Immunoreactivity was then measured using a specialized software called ImageJ.⁷  Results:  The successful injection of pericytes into mouse brain tissue was confirmed by higher levels of immunoreactivity of PDGFR β, a pericyte marker, at the injection site compared to the contralateral control injection site. Furthermore, immunoreactivity with collagen IV demonstrated that the pericytes associated with blood vessels. Three weeks following pericyte implantation, LASCA showed that the brain microcirculation was significantly improved at the pericyte injection site compared to the contralateral control site. Additionally, ELISA revealed that the levels of insoluble Aβ40 and Aβ42 were markedly lower in the hippocampus of the pericyte-injected hemisphere compared to the contralateral side suggesting that pericyte implantation reduced Aβ deposition in the hippocampus.⁷  Conclusions:  The key to curing Alzheimer’s may lie in restoring the BBB.⁷ Mesenchymal stem cell therapy shows promise in reestablishing pericyte function and numbers, thereby improving cerebral blood flow.^7,9 Pericytes are also shown to reduce beta-amyloid plaque accumulation in brain parenchyma.⁷ Collectively, these results may restore neural synapses and improve cognitive function in patients with Alzheimer’s Disease.^7,9

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9. Matchynski-Franks J, Pappas C, Rossignol J, et al. Mesenchymal Stem Cells as Treatment for Behavioral Deficits and Neuropathology in the 5xFAD Mouse Model of Alzheimer’s Disease. Cell Transplantation. 2016; Vol 25, pp. 687-703.