A physically-modified saline suppresses neuronal apoptosis, attenuates tau phosphorylation and protects memory in an animal model of Alzheimer's disease.

Khushbu K Modi,Arundhati Jana,Kalipada Pahan,Supurna Ghosh,Richard Watson,Brij Singh

doi:10.1371/journal.pone.0103606

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.

Highlights

Alzheimer’s disease (AD) [1] is a neurodegenerative disorder, resulting in progressive neuronal death and memory loss
Neuritic plaques are composed of aggregates of Ab protein, a 40–43 amino acid proteolytic fragment derived from the amyloid precursor protein that is over-expressed in AD while NFTs are composed of hyperphosphorylated microtubule- associated protein tau [1,2]
Because the fibrillar form of Ab is commonly found in the senile plaques in AD brains [1] and is known to cause neuronal death, we first examined whether fibrillar Ab1–42 was capable of inducing apoptosis in the SHSY5Y cell line in our experimental setting

Summary

Introduction

Alzheimer’s disease (AD) [1] is a neurodegenerative disorder, resulting in progressive neuronal death and memory loss. Neuritic plaques are composed of aggregates of Ab protein, a 40–43 amino acid proteolytic fragment derived from the amyloid precursor protein that is over-expressed in AD while NFTs are composed of hyperphosphorylated microtubule- associated protein tau [1,2]. Multiple lines of evidence demonstrate that errors in the regulation of either tau or the amyloid precursor protein result in neuronal death and cognitive dysfunction in humans [3,4,5]. Experiments in both cultured rodent hippocampal neurons and transgenic mice demonstrate that Ab-mediated neuronal death, learning and memory impairments require tau [6,7]

Methods

Results

Conclusion