Magnesium Modulates Amyloid-β Protein Precursor Trafficking and Processing

Alzheimer's disease (AD), the most common form of dementia, is characterized by the presence of excessive deposits of aggregated amyloid-beta (A beta), which is derived from the amyloid-beta protein precursor (A beta PP) 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 A beta PP processing and A beta secretion. Here we show the effects of varying [Mg2+](o) on A beta PP processing is time-and dose-dependent. After 24 h treatment, high [Mg2+](o) increased C-terminal fragment-alpha (CTF alpha) levels and soluble alpha-secretase cleaved A beta PP (sA beta PP alpha) release via enhancing retention of A beta PP on plasma membrane. In contrast, low [Mg2+](o) enhanced CTF beta accumulation and A beta secretion, and reduced cell surface A beta PP level. Varying [Mg2+](o) did not alter protein contents of full length A beta PP. However, decreased total intracellular magnesium level by magnesium deprivation over 24 hr impaired cell viability. Normal A beta PP processing could be restored when magnesium was adjusted back to physiological concentration. These data demonstrate that A beta PP processing can be modulated by magnesium and at high [Mg2+](o), A beta PP processing favors the alpha-secretase cleavage pathway. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD.