Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated yet. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-β, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation, and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…These unsatisfactory effects force people to pay attention on more targeted and etiology-oriented strategies [116]. Due to the notion that age-related oxidative stress has been acknowledged as one of the major risk factors of AD pathogenesis and the early manifestation of AD [18], anti-aging drugs (antioxidants) have become the prevailing therapeutic strategy against AD. In this respect, yeasts, relatively simple unicellular organisms, vigorously growing on simple and inexpensive media may be exceptionally promising models for searching for and treating the newly synthesized effective antioxidants, especially mitochondria-targeted antioxidants [109,[117][118][119].…”

“…Moreover, oxidative stress is also the major cause of glial inflammation and apoptosis. All these findings suggest a critical role for oxidative stress in promoting AD and highlight the for antioxidants as potential drugs for combating AD [17][18][19][20][21][22][23].…”

“…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...…”

A Critical Assessment of Research on Neurotransmitters in Alzheimer’s Disease

“…Lan Guo and colleagues discuss the association between mitochondrial dysfunction and synaptic transmission deficits in AD [21]. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, and excess mitochondrial reactive oxygen species (ROS) generation and release play important roles in mediating the deregulation of synaptic transmission in AD.…”

“…They also explain mechanisms by which synapses are injured in particular AD-related conditions. They suggest that a better understanding of mitochondrial dysfunction and synaptic stress in AD may lead to therapeutic strategies that target mitochondrial deficits and that protect synaptic transmission known to be affected in AD [21]. …”