Abstract
Alzheimer’s disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, is characterized by the progressive loss of neurons and synapses, the accumulation of intracellular neurofibrillary tangles that are primarily composed of hyperphosphorylated tau and extracellular senile plaques that are primarily composed of b-amyloid [1,2,3]
AD is an age-related degenerative disease that is characterized by progressive dementia
These facts highlight the need to search for treatments that act on selective targets during the silent period of the disease, which are aimed at retarding disease progression toward dementia [48,49]
Summary
Alzheimer’s disease (AD), the most common form of dementia, is characterized by the progressive loss of neurons and synapses, the accumulation of intracellular neurofibrillary tangles that are primarily composed of hyperphosphorylated tau and extracellular senile plaques that are primarily composed of b-amyloid [1,2,3]. The molecular mechanisms underlying tau hyperphosphorylation and b-amyloid aggregation have been studied extensively [4,5]; the exact etiopathogenesis of AD is poorly understood. The great majority of AD cases occur sporadically at a late stage of life, while aging and metabolic disorders including Type 2 diabetes (T2DM) are the main non-genetic risk factors [6]. AD is associated with impaired glucose metabolism and insulin resistance in the brain. T2DM and AD share several common abnormalities, including aging-related processes, high cholesterol levels, metabolic disorders, Ab aggregation, tau protein phosphorylation, glycogen synthase kinase-3 (GSK-3) over-activation, insulin resistance and the induction of oxidative stress [12,13,14,15]. An intracerebroventricular (ICV) infusion of streptozotocin (STZ) is a valid experimental model to explore the etiology of sAD [16]; the mechanisms underlying ICV STZ-induced AD-like pathological changes remain elusive
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