Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

Abstract

Significance: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-b [Ab]) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances: A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical Issues: In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Ab and tau in the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio ''aging, Ab, and tau protein'' triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation (OXPHOS), elevation of reactive oxygen species production, and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions: The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Ab and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon.

The neuroprotective potential of phenolic-enriched fractions from four Juniperus species found in Portugal

“…Research in recent years has provided substantial evidence supporting the theory that oxidative stress plays a major role in the pathogenesis of neurodegenerative disease (Mulero, Zafrilla, & Martinez-Cacha, 2011;Schmitt et al, 2011;Shadrina, Slominsky, & Limborska, 2010). Oxidative stress is primarily caused by deviation of the cells redox balance from the norm and generally this is associated with an excessive accumulation of reactive oxygen species (ROS) in cells; a process previously implicated in the development of many neurodegenerative diseases including Parkinson's disease (PD), Huntington's disease, amyotrophic lateral sclerosis and AD (Gandhi & Wood, 2005;Lin & Beal, 2006;Shadrina et al, 2010).…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Dysfunctions in glucose metabolism, bioenergetics, and mitochondrial function are consistent antecedents leading to AD pathology, including Aβ plaque and neurofibrillary tangles [11]. Dysfunctional mitochondria produce high levels of reactive oxygen species (ROS); these ROS can negatively affect specific mitochondrial components, including mitochondrial DNA (mtDNA), membrane lipids, and oxidative phosphorylation proteins [18,19]. For example dysregulation of complex I has been correlated with tau toxicity, and dysregulation of complex IV has been associated with increased Aβ load [20][21][22].…”

Improvement of neuronal bioenergetics by neurosteroids: Implications for age-related neurodegenerative disorders

“…Mitochondria are not only the "powerhouses of the cell", providing the main source of cellular energy via ATP generation through oxidative phosphorylation, but they also contribute to plenty of cellular functions, including apoptosis, intracellular calcium homeostasis, alteration of the cellular reduction-oxidation (redox) state and synaptic plasticity [3,4]. Thus, it is more and more recognized that mitochondrial dysfunction is a significant and early event of neurodegeneration, and that the pathophysiological mechanisms of a range of neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's disease (PD), are associated with a decline in bioenergetic activity and an increase in oxidative stress, particularly in mitochondria themselves [5][6][7][8][9][10].…”