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Magnesium modulates amyloid-beta protein precursor trafficking and processing.

Abstract

Alzheimer’s disease (AD), the most common form of dementia, is characterized by the presence of excessive deposits of aggregated amyloid-beta (Abeta), which is derived from the amyloid-beta protein precursor (AbetaPP) following processing by beta- and gamma-secretase. Metal elements are implicated in the pathophysiology of AD. Magnesium affects many biochemical mechanisms vital for neuronal properties and synaptic plasticity, and magnesium levels were reported to be decreased in various tissues including brain of AD patients. However, the exact role of magnesium in the neurodegenerative process of AD remains elusive. In this study, we investigated the effects of physiological (0.8 mM, as normal control), low (0-0.4 mM), and high (1.2-4.0 mM) concentrations of extracellular magnesium ([Mg2+]o) on AbetaPP processing and Abeta secretion. Here we show the effects of varying [Mg2+]o on AbetaPP processing is time- and dose-dependent. After 24 h treatment, high [Mg2+]o increased C-terminal fragment-alpha (CTFalpha) levels and soluble alpha-secretase cleaved AbetaPP (sAbetaPPalpha) release via enhancing retention of AbetaPP on plasma membrane. In contrast, low [Mg2+]o enhanced CTFbeta accumulation and Abeta secretion, and reduced cell surface AbetaPP level. Varying [Mg2+]o did not alter protein contents of full length AbetaPP. However, decreased total intracellular magnesium level by magnesium deprivation over 24 hr impaired cell viability. Normal AbetaPP processing could be restored when magnesium was adjusted back to physiological concentration. These data demonstrate that AbetaPP processing can be modulated by magnesium and at high [Mg2+]o, AbetaPP processing favors the alpha-secretase cleavage pathway. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD.

Yu, J., Sun, M., Chen, Z., Lu, J., Liu, Y., Zhou, L., … & Chui, D. (2010). Magnesium modulates amyloid-β protein precursor trafficking and processingJournal of Alzheimer’s Disease20(4), 1091-1106.