Alzheimer’s disease

Alzheimer’s disease

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Abstract

Alzheimer's disease (AD), the leading cause of dementia in the ageing 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.

Results

RNS60 protects human SHSY5Y neuronal cells against Aβ toxicity

Because the fibrillar form of Aβ is commonly found in the senile plaques in AD brains [1] and is known to cause neuronal death, we first examined whether fibrillar Aβ1–42 was capable of inducing apoptosis in the SHSY5Y cell line in our experimental setting. As demonstrated in figure 1B, fibrillar Aβ1–42 peptide, but not the reverse Aβ42–1 peptide, markedly induced the formation of apoptotic bodies after 6 h of stimulation as seen by TUNEL staining. Pretreatment of SHSY5Y cells for 1 h with RNS60 inhibited Aβ- induced apoptosis in a dose dependent manner, while pretreatment with different doses of NS did not show any protective effect in Aβ-treated cells (Fig. 1B–C). We also examined the protective effect of RNS60 against Aβ-induced neurotoxicity using the MTT and LDH release assays. RNS60 and NS alone did not alter the MTT metabolism (Fig. 1D), suggesting that these saline solutions were not toxic to neuronal cells. Aβ significantly decreased the viability of SHSY5Y cells as monitored by a decrease in MTT metabolism (Fig. 1E) and an increase in LDH release (Fig. 1F). RNS60 effectively reduced the Aβ-induced loss of MTT metabolism as well as the increased LDH (Fig. 1E–F). In contrast, NS, PNS60 (saline containing excess oxygen in the absence of TCP modification) or RNS10.3 (TCP-modified saline without excess oxygen) failed to rescue the Aβ-induced loss of cell viability (Fig. 1E–F). It is known that caspase-3 activation plays a crucial role in apoptosis. As evident from figure 2A–B, RNS60 treatment caused a decrease in the proteolytically active form of caspase-3 after 4 h of Aβ stimulation while NS, PNS60 and RNS10.3 were ineffective.

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Alzheimer’s disease

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