Magnesium Modulates Amyloid-β 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-β (Aβ), which is derived from the amyloid-β protein precursor (AβPP) following processing by β- and γ-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 AβPP processing and Aβ secretion. Here we show the effects of varying [Mg²⁺]_o on AβPP processing is time- and dose-dependent. After 24 h treatment, high [Mg²⁺]_o increased C-terminal fragment-α (CTFα) levels and soluble α-secretase cleaved AβPP (sAβPPα) release via enhancing retention of AβPP on plasma membrane. In contrast, low [Mg²⁺]_o enhanced CTFβ accumulation and Aβ secretion, and reduced cell surface AβPP level. Varying [Mg²⁺]_o did not alter protein contents of full length AβPP. However, decreased total intracellular magnesium level by magnesium deprivation over 24 hr impaired cell viability. Normal AβPP processing could be restored when magnesium was adjusted back to physiological concentration. These data demonstrate that AβPP processing can be modulated by magnesium and at high [Mg²⁺]_o, AβPP processing favors the α-secretase cleavage pathway. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD.