A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

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.

Plasma Glutathione Levels Decreased with Cognitive Decline among People with Mild Cognitive Impairment (MCI): A Two-Year Prospective Study

“…In accordance with the findings from previous AD patients or non-demented individuals [ 15 , 17 , 18 , 19 , 22 ], the current study demonstrated that both plasma GSH levels (from 4.1 ± 2.5 at baseline to 2.2 ± 2.7 ng/mL at endpoint ( p < 0.001)) and cognitive function (mean ADAS-cog score from 9.4 ± 7.1 to 11.1 ± 9.1 ( p = 0.035); and MMSE from 25.3 ± 3.8 to 24.0 ± 4.1 ( p = 0.006)) declined 2 years later among the patients with MCI ( Table 2 ). In contrast, among the healthy elderly, the GSH levels, albeit with fluctuation, did not change significantly between baseline (4.1 ± 2.7 ng/mL) and endpoint (3.0 ± 3.1 ng/mL), while their cognitive function also remained stable (ADAS-cog score from 3.5 ± 1.7 to 3.1 ± 1.6; MMSE from 28.7 ± 1.1 to 28.3 ± 1.2) ( Table 2 ).…”

“…Glutathione (GSH), a major endogenous antioxidant present in all mammalian cells and peripheral blood, plays a vital role in protecting neuronal cells from oxidative stress [ 14 , 15 ]. GSH scavenges harmful reactive oxygen species that are generated during different cellular/molecular processes including neurodegeneration [ 16 ].…”

“…Several studies have shown GSH redox imbalance in AD and decreased GSH levels in AD animal models as well as in the brain and blood of AD patients [ 15 , 17 , 18 , 19 ]. Though not all AD patients showed different GSH levels with normal controls [ 20 , 21 ], lower GSH concentration was associated with severer cognitive impairment among AD patients [ 20 ].…”

Effects of Vitamin D3 and Meso-Zeaxanthin on Human Retinal Pigmented Epithelial Cells in Three Integrated in vitro Paradigms of Age-Related Macular Degeneration

“…Our findings about vitamin D 3 activity on ARPE-19 cells challenged with H 2 O 2 and LPS are supported by recent findings on 1,25(OH) 2 D 3 antioxidant and anti-inflammatory activity (Fernandez-Robredo et al, 2020;Hernandez et al, 2021). Preclinical and clinical studies evidenced protective effects of vitamin D 3 in Alzheimer disease, an amyloid-β-related pathology (Sultan et al, 2020;McCarty et al, 2021). The link between AMD and AD pathology has been largely documented (Romano et al, 2017), and low-vitamin D 3 levels in serum were linked to progression of AMD, however with small effect (i.e., small adjusted odd ratio) (McKay et al, 2017).…”

Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

“…Therefore, oxidative stress can be considered one of the factors responsible for the accumulation of Aβ. Oxidizing agents increase the expression of APP [ 104 ] and increase the intracellular and secreted Aβ levels [ 99 ]. We, along with other authors, have shown that the expression and activity of BACE 1 increased in conditions of oxidative stress [ 105 , 106 , 107 , 108 , 109 ].…”