Abstract
Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer’s disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid β generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid β on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid β oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid β monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1β, which potentiates the neurotoxicity of amyloid β. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further.
Highlights
Sci. 2021, 22, x FOR PEERoRxEiVdIaEnWt production stemming from NADPH oxidase; this phenomenon may ind2uofc2e7 the mitochondrial fission that is typically seen in Alzheimer’s disease (AD) neurons [4]
Brain and CSF levels of BACE1 have been found to be elevated in AD patients and to correlate with brain amyloid load and decrease in hippocampus volume, and though increased generation of amyloid β is clearly the driving pathogenic factor in early-onset AD patients carrying certain variant genes, a classic study comparing brain turnover of amyloid β in patients with sporadic AD and healthy controls concluded that a diminished capacity to catabolize or export amyloid β is the chief reason why amyloid β accumulates in the brain of sporadic AD patients [145,146,147,148,149,150]
Amyloid β oligomers act on brain capillary cells to suppress expression of both lipoprotein receptor-related protein 1 (LRP1) and of P-glycoprotein (P-GP); LRP1 acts in the abluminal capillary membrane to extract amyloid β monomers/oligomers from the brain extracellular space, and P-G acts on the luminal side to expel them into the circulation [177,178,179,180,181,182,183]
Summary
Via direct interaction and/or the ability of amyloid β oligomers to inhibit mechanisms of glutamate uptake by astrocytes and pre-synaptic membranes—resulting in extrasynaptic accumulation of glutamate—amyloid β activates extrasynaptic NMDA receptors, leading to an influx of calcium and a concurrent activation of NOX2-dependent NADPH oxidase complexes within their microenvironment [1,2,3]. These locally generated oxidants can oxidize ryanodine receptors (RYR2) in nearby endoplasmic reticulum (ER), such that they are far more likely to open in response to the modest calcium influx mediated by NMDA receptor activation [4]. A partial reduction of tau expression is protective in AD model mice
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