Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…Numerous research teams have adduced evidence supporting a direct causal relationship between oxidative stress and the development of synaptic dysfunction in AD [232]; reviewed by [233]. This is also true of mitochondrial dysfunction and glucose hypometabolism which is apparent in the posterior cingulate cortex and other AD-vulnerable brain regions in MCI patients and healthy adult carriers of APOE ε4 many years or even decades before the development of clinical symptoms and, crucially, before any discernible evidence of tau or Aβ pathology [234,235]; reviewed by [236].…”

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

“…Altered energy production and increased generation of reactive oxygen species (ROS) is well documented in AD (Tonnies and Trushina, 2017). Interestingly, while the presence of Aβ plaques is essential for AD diagnosis, Aβ peptides may not be a primary cause of neurodegeneration (Jack Jr et al, 2014).…”

“…Increased production of ROS by dysfunctional mitochondria could activate pathological cascade of events known as a “vicious cycle” inducing greater severity of metabolic and epigenetic alterations. This, in turn, could affect multiple essential neuronal functions including an abnormal APP processing and the generation of toxic Aβ peptides, ultimately leading to the loss of cognitive function (Pimplikar et al, 2010; Swerdlow et al, 2014; Tonnies and Trushina, 2017; Yu et al, 2016). Moreover, once produced, Aβ peptides could exacerbate mitochondrial dysfunction by incorporating into the organelle and affecting their protein import and ATP production, further enhancing generation of ROS and Aβ (Chen and Yan, 2010; Hansson Petersen et al, 2008a; Mossmann et al, 2014).…”

Disruption of Neurosynaptic Physiology and Neuron Network Dysfunction in Brain Disorders: An Environmental and Occupational Health Perspective

“…Many of environmental pollutants are oxidative agents acting through different mechanisms. Brain is particularly vulnerable to oxidative stress due to its highly glucose based metabolic rate, low levels of antioxidants, high levels of polyunsaturated fatty acids and high enzymatic activities related to transition metals that catalyse formation of free radicals [154].…”