Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

Abstract

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

Cognitive Impairment in Multiple Sclerosis

“…In patients with optic neuritis [165,166], a common occurrence in almost half of patents with MS. APOE serum levels were significantly higher than in control patient groups and the APOE ε3/ε3 genotype may increase the risk of developing optic neuritis in males [167]. In addition to APOE-ε4, MS may share other cellular pathways with AD that lead to cognitive loss such as Aβ [37,102,[168][169][170][171][172]. In studies that examine cerebrospinal fluid biomarkers, changes in Aβ 42 as seen in AD can also predict early cognitive decline in MS [173].…”

“…In general, autophagy consists of the recycling of cytoplasmic organelles and proteins that can lead to the remodeling and formation of new tissue structures [34,44,61,100,169,202,[242][243][244][245]. Although the process of macroautophagy is usually described, other subsets of autophagy exist that include microautophagy and chaperone-mediated autophagy.…”

“…In addition, during infections, the autophagy-lysosome pathway can increase inflammatory reactions. An example of this is the severe acute respiratory syndrome coronavirus (SARS-CoV-2) [85,110,115,169,239,251,256,257]. Recent work has shown that exposure to infectious agents, such as SARS-CoV-2 as part of coronavirus disease 2019 (COVID-19), may lead to increased death rates in patients with MS [258].…”

“…This process of caspase activation and DNA destruction is irreversible [259]. Limiting apoptotic cell death may minimize memory loss and cognition during both acute and chronic insults [34,93,96,169,172,185,276,279]. This may occur during measures that reduce inflammatory pathways and affect neuronal and oligodendrocyte survival [9,108,132,187,252,276,[279][280][281][282], as well as cognitive performance [25,[283][284][285].…”

“…Increased inflammasome expression has been associated with potential treatment failures in MS patients [286], as well as the increased inflammatory activity of cytokine release and immune cell activity in experimental models [134]. Pyroptosis is a programmed cell death pathway that can oversee inflammatory cell activation in the nervous system [34,66,169,212,213]. Pyroptosis is initiated with the production of a supramolecular complex, known as the pyroptosome or the inflammasome.…”