Cerebrospinal Fluid (CSF) Exchange Therapy with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Cognitive Deficits and Brain Pathology in Alzheimer's Disease Mice

Background: The high complexity of neurodegenerative diseases, including Alzheimer's disease (AD), and the lack of effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. Objective: To test the efficacy of `cerebrospinal fluid (CSF) exchange therapy' in AD-mice. This novel therapeutic approach we recently proposed is based on the exchange of the endogenous pathogenic CSF with a new and healthy one by drainage of the endogenous CSF and its continuous replacement with artificial CSF (aCSF) enriched with secretions from human mesenchymal stem cells (MSCs). Methods: We treated AD-mice (amyloid-beta injected) with MSC secretions-enriched-aCSF using an intracerebroventricular CSF exchange procedure. Cognitive and histological analysis were performed. Results: We show that the MSC secretions enriched CSF exchange therapy improved cognitive performance, paralleled with increased neuronal counts (NeuN positive cells), reduced astrocytic burden (GFAP positive cells), and increased cell proliferation and neurogenesis (Ki67 positive cells and DCX positive cells) in the hippocampus. This beneficial effect was noted on days 5-10 following 3-consecutive daily exchange treatments (3 hours a day). A stronger effect was noted using a more prolonged CSF exchange protocol (3-consecutive daily exchange treatments with 3 additional treatments twice weekly), with cognitive follow-up performed as early as 2-3 days after treatment. Some increase in hippocampal cell proliferation, but no change in the other histological parameters, was noticed when performing CSF exchange therapy using unenriched aCSF relative to untreated AD-mice, yet smaller than with the enriched aCSF treatment. Conclusion: These findings point to the therapeutic potential of the CSF exchange therapy using MSC secretions-enriched aCSF in AD, and might be applied to other neurodegenerative and dementia diseases.