title: A physically-modified saline suppresses neuronal apoptosis, attenuates tau phosphorylation and protects memory in an animal model of Alzheimer's disease.
abstract: Alzheimer's disease (AD), the leading cause of dementia in the aging population, is characterized by the presence of neuritic plaques, neurofibrillary tangles and extensive neuronal apoptosis. Neuritic plaques are mainly composed of aggregates of amyloid-β (Aβ) protein while neurofibrillary tangles are composed of the hyperphosphorylated tau protein. Despite intense investigations, no effective therapy is currently available to halt the progression of this disease. Here, we have undertaken a novel approach to attenuate apoptosis and tau phosphorylation in cultured neuronal cells and in a transgenic animal model of AD. RNS60 is a 0.9% saline solution containing oxygenated nanobubbles that is generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. In our experiments, fibrillar Aβ1-42, but not the reverse peptide Aβ42-1, induced apoptosis and cell death in human SHSY5Y neuronal cells. RNS60, but not NS (normal saline), RNS10.3 (TCP-modified saline without excess oxygen) or PNS60 (saline containing excess oxygen without TCP modification), attenuated Aβ(1-42)-induced cell death. RNS60 inhibited neuronal cell death via activation of the type 1A phosphatidylinositol-3 (PI-3) kinase-Akt-BAD pathway. Furthermore, RNS60 also decreased Aβ(1-42)-induced tau phosphorylation via (PI-3 kinase-Akt)-mediated inhibition of GSK-3β. Similarly, RNS60 treatment suppressed neuronal apoptosis, attenuated Tau phosphorylation, inhibited glial activation, and reduced the burden of Aβ in the hippocampus and protected memory and learning in 5XFAD transgenic mouse model of AD. Therefore, RNS60 may be a promising pharmaceutical candidate in halting or delaying the progression of AD.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Khushbu K
authors.initials: KK
authors.lastname: Modi
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Jana
authors.affiliation: Revalesio Corporation, Tacoma, Washington, United States of America.
authors.forename: Supurna
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Revalesio Corporation, Tacoma, Washington, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Watson
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D000682:Amyloid / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012965:Sodium Chloride / Q000494:pharmacology*; D065853:Spatial Learning / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016875:tau Proteins; D012965:Sodium Chloride; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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