Abstract
As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.
Highlights
The mitochondrial electron transport chain (ETC) consists of several of protein complexes situated in the inner mitochondrial membrane (IMM) which use the electrons removed by reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2 ) from the Krebs cycle to pump protons from the matrix into the intermembrane space, thereby generating a potential gradient across the IMM, which will be used in the final step of oxidative phosphorylation (OXPHOS) to synthesize ATP [56]
The many pathways leading to increased ROS generation and their consequences apply to all cells, each neurodegenerative disease leads to degeneration of particular groups of neurons, which led researchers to look for explanations for this selective vulnerability of neuronal populations
From the repeated failures of drugs targeting mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, it appears that starting these interventions by the time of clinical diagnosis is probably too late
Summary
Aging of the brain occurs at molecular, cellular, and histological levels [2]. It associates lower levels of neuronal metabolic activity, subtle alterations in neuronal structure in several neuronal circuits, as well as synaptic atrophy, cytoskeletal abnormalities, accumulation of fluorescent pigments, and reactive astrocytes and microglia [3,4]. Mitochondria undergo a series of age-related changes such as fragmentation or enlargement [25], increased mitochondrial DNA (mtDNA) oxidative damage [26], exhibit dysfunctions of the respiratory chain [27] and of calcium homeostasis [28]. These changes associate a reduction of the intracellular NAD+ levels which impairs the function of NA dependent enzymes such as sirtuins (SIRT) and histone deacetylases [29,30]. The secretory phenotype associated with senescence (SASP), in astrocytes, can trigger several age-related neurodegenerative diseases [48]
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