Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder. Extracellular aggregates of amyloid precursor protein (APP), called Aβ peptide and neurofibrillary tangles (NFTs), formed by tau protein in the hyperphosphorylated form are considered the hallmarks of AD. Accumulative evidence suggests that tau pathology and Aβ affect neuronal cells compromising energy supply, antioxidant response, and synaptic activity. In this context, it has been showed that mitochondrial function could be affected by the presence of tau pathology and Aβ in AD. Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration. Several reports have suggested that mitochondria could be affected in terms of morphology, bioenergetics, and transport in AD. These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD. In this review, we will discuss evidence that supports the importance of mitochondrial injury in the pathogenesis of AD and how studying these mechanisms could lead us to suggest new targets for diagnostic and therapeutic intervention against neurodegeneration.

The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

“…Thus, detachment of HK from VDAC1 by A␤ could lead to increased ROS generation and release to the cytoplasm, subsequently activating cell death. An association between ␤-amyloid toxicity, mitochondrial dysfunction, oxidative stress, and neuronal damage and death in Alzheimer disease is well established (70). Thus, by preventing A␤ cell penetration with siRNA or VDAC1-N-terminal peptide, A␤-induced HK detachment would be prevented as well as subsequent effects on cell energy impairment and apoptosis induction (Fig.…”

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…In addition, neurons are exceedingly compartmentalized, comprising structures like: cell body, axon, dendrites and even more specific compartments that are the synapses, which makes a proper mitochondrial distribution pivotal to sustaining the energy requirement at specific locations within the different neuronal compartments [31,35,36]. The crucial role of mitochondria in supporting synaptic function and the concomitant occurrence of impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess of mitochondrial ROS generation and release with mediating synaptic transmission deregulation in AD seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD [32][33][34]37,41,43,47].…”

“…Evidence is presented suggesting amyloid oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, additional cofactors are required [13]. Those cofactors include several subcellular processes including oxidative damage [10,[14][15][16][17][18][19][20][21][22][23], recruitment of peripheral immune cells and excessive production of pro-inflammatory mediators [10,[24][25][26][27][28][29], mitochondrial impairments and chronic energy imbalance [12,20,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], chronic endoplasmic reticulum (ER) stress [48] and autophagy dysfunction [22,[49][50][51][52][53][54], the abnormality and dysfunction of MAM (the mitocho...…”

The Hormesis of Thinking: A Deeper Quantum Thermodynamic Perspective?

“…Hence, continued neuroinflammation could have devastating effects on the cohesive structure of the brain. In fact astrocytes and microglial cells can end up in a reactive gliosis "vicious cycle", which is thought to be involved in the progression of neurodegenerative disorders [134] conditions known to be associated with mitochondrial "dysfunction" [135]. In fact many disorders are associated with an imbalance between mitochondrial fission and fusion, and in general, the balance is more towards fission and the loss of networks; this could reflect the shift of cells towards proliferation and glycolysis [136].…”