Rebalancing β-Amyloid-Induced Decrease of ATP Level by Amorphous Nano/Micro Polyphosphate: Suppression of the...

Morbus Alzheimer neuropathology is characterized by an impaired energy homeostasis of brain tissue. We present an approach towards a potential therapy of Alzheimer disease based on the high-energy polymer inorganic polyphosphate (polyP), which physiologically occurs both in the extracellular and in the intracellular space. Rat pheochromocytoma (PC) 12 cells, as well as rat primary cortical neurons were exposed to the Alzheimer peptide Aβ25-35. They were incubated in vitro with polyphosphate (polyP); ortho-phosphate was used as a control. The polymer remained as Na⁺ salt; or complexed in a stoichiometric ratio to Ca²⁺ (Na-polyP[Ca²⁺]); or was processed as amorphous Ca-polyP microparticles (Ca-polyP-MP). Ortho-phosphate was fabricated as crystalline Ca-phosphate nanoparticles (Ca-phosphate-NP). We show that the pre-incubation of PC12 cells and primary cortical neurons with polyP protects the cells against the neurotoxic effect of the Alzheimer peptide Aβ25-35. The strongest effect was observed with amorphous polyP microparticles (Ca-polyP-MP). The effect of the soluble sodium salt; Na-polyP (Na-polyP[Ca²⁺]) was lower; while crystalline orthophosphate nanoparticles (Ca-phosphate-NP) were ineffective. Ca-polyP-MP microparticles and Na-polyP[Ca²⁺] were found to markedly enhance the intracellular ATP level. Pre-incubation of Aβ25-35 during aggregate formation, with the polyP preparation before exposure of the cells, had a small effect on neurotoxicity. We conclude that recovery of the compromised energy status in neuronal cells by administration of nontoxic biodegradable Ca-salts of polyP reverse the β-amyloid-induced decrease of adenosine triphosphate (ATP) level. This study contributes to a new routes for a potential therapeutic intervention in Alzheimer's disease pathophysiology.