Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy

Abstract

Aging and average life expectancy have been increasing at a rapid rate, while there is an exponential risk to suffer from brain-related frailties and neurodegenerative diseases as the population ages. Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide with a projected expectation to blossom into the major challenge in elders and the cases are forecasted to increase about 3-fold in the next 40 years. Considering the etiological factors of AD are too complex to be completely understood, there is almost no effective cure to date, suggesting deeper pathomechanism insights are urgently needed. Metabolites are able to reflect the dynamic processes that are in progress or have happened, and metabolomic may therefore provide a more cost-effective and productive route to disease intervention, especially in the arena for pathomechanism exploration and new biomarker identification. In this review, we primarily focused on how redox signaling was involved in AD-related pathologies and the association between redox signaling and altered metabolic pathways. Moreover, we also expatiated the main redox signaling-associated mechanisms and their cross-talk that may be amenable to mechanism-based therapies. Five natural products with promising efficacy on AD inhibition and the benefit of AD intervention on its complications were highlighted as well. Graphical Abstract

The biological pathways of Alzheimer disease: a review

“…These deposits coalesce to form the miliary structures that are known as plaques [7] . Interestingly, recent data suggest the importance of cholesterol for the γ-secretase cleavage of amyloid precursor protein, the last step of Aβ formation [32] .…”

“…Indeed, recent observations indicated that Pre-translational mRNA oxidation synthetize peptides that are prone to aggregate [199] . mRNA oxidation seems to be a cytoanatomically selective event that hit mRNAs translated by ribosomes that reside tethered to the mitochondrial outer membrane [32] . The aggregates heavily impair the physiological cell functions.…”

“…From a molecular point of view, glucose hypometabolism is likely linked with OS. For instance, it was observed that the expression and function of key enzymes in the glycolytic cascade is reduced with high ROS levels [32] , [216] , [217] . Energy alterations were also linked to a decreased functionality of enzymes related to TCA cycle, which lead neurons to a hypometabolic state [200] , [218] – [222] .…”

“…In particular, it was observed that the amyloidogenic protein and its precursors have the ability to bind metals [130] . At the same time, bound metals can force proteins to alter their conformations [326] , promoting metal-Aβ complexes generation and AD progression [32] . Aβ oligomerization reduces the availability of free metal ions.…”

“…It was demonstrated that deficiency of these metals produces severe adverse effects on central nervous system functions, especially learning and memory, functions intimately linked with AD development. Metal levels increase promote several pro-OS reactions and lead to (1) ROS generation through a Fenton-like mechanism [32] , [189] , [331] , [332] (2) increased ROS lifetime [333] and (3) oxidative phosphorylation decrease in mitochondria [32] .…”