Mitochondrial dysfunction in Alzheimer’s disease - a proteomics perspective

Abyadeh, Morteza; Gupta, Vivek Kumar; Chitranshi, Nitin; Gupta, Veer; Wu, Yunqi; Saks, Danit; Wall, Roshana Wander; Fitzhenry, Matthew J.; Basavarajappa, Devaraj; You, Yuyi; Salekdeh, Ghasem Hosseini; Haynes, Paul A.; Graham, Stuart L.; Mirzaei, Mehdi

doi:10.1080/14789450.2021.1918550

Cited by 35 publications

(29 citation statements)

References 106 publications

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“…Several studies have revealed a higher occurrence of both nuclear and mtDNA mutations in AD brains [42,43]. Genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), APP, tau, and APOE4 genes are strongly associated with Aβ aggregation and AD development [28,44]. Among these genes, mutations in APP (21q21), PSEN1 (14q24), and PSEN2 (1q42) are fully penetrant and follow an autosomal dominant inheritance pattern, resulting in aggressive forms of early-onset AD that account for approximately 5% of all AD cases [45].…”

Section: Genetically Induced Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Studies have highlighted the presence of damaged mitochondria near synapses resulting from various insults, including accrued Aβ oligomers or fibrils and phosphorylated tau. Conversely, dysfunction due to mitochondrial DNA (mtDNA) damage, mutations, or impaired transport of metabolites and proteins may lead to Aβ oligomeric or fibrillar formation and phosphorylated tau accumulation [28]. Thus, accrued mitochondrial damage due to insults such as oxidative stress and accumulation of Aβ oligomers may act synergistically to further damage mitochondria and drive AD pathology [27].…”

Section: Introductionmentioning

confidence: 99%

“…Several recent studies have highlighted the involvement of mitochondrial dysfunction in AD [26][27][28][29]. Besides, availability of information related to mitochondrial proteomic has opened the door that uncovers various aspects of this energy associated organelle, which further adds on the understanding of mitochondrial dysfunction in AD [28]. Thus, sustaining mitochondrial function therapeutically may forestall neurodegeneration and loss of cognition in AD [30,31].…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

Sharma

Kim

Nam

et al. 2021

IJMS

112

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Alzheimer’s disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aβ is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-β precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.

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Section: Genetically Induced Mitochondrial Dysfunctionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

Sharma

Kim

Nam

et al. 2021

IJMS

112

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“…It was suggested that increased protein expression may be a compensatory response to THC exposure, which adversely affected neuronal bioenergetics. Additionally, P120 showed 186 DEPs, 49 of which were up-regulated mitochondrial proteins, indicating long-lasting effects of THC on neuronal bioenergetics [83,103,104]. Collectively, the results of the proteomic studies discussed above show dysfunctional neuronal mitochondrial biogenesis, as well as impaired neuronal cytoskeleton growth and development, as the main consequences of THC toxicity.…”

Section: Proteomic Studies On Tetrahydrocannabinolmentioning

confidence: 94%

A Proteomic View of Cellular and Molecular Effects of Cannabis

Abyadeh¹,

Gupta

Paulo

et al. 2021

Biomolecules

Self Cite

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Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known as cannabinoids against several diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease, schizophrenia and glaucoma; these have prompted changes in medicinal cannabis legislation. The relaxation of legal restrictions and increased socio-cultural acceptance has led to its increase in both medicinal and recreational usage. Several biochemically active components of cannabis have a range of effects on the biological system. There is an urgent need for more research to better understand the molecular and biochemical effects of cannabis at a cellular level, to understand fully its implications as a pharmaceutical drug. Proteomics technology is an efficient tool to rigorously elucidate the mechanistic effects of cannabis on the human body in a cell and tissue-specific manner, drawing conclusions associated with its toxicity as well as therapeutic benefits, safety and efficacy profiles. This review provides a comprehensive overview of both in vitro and in vivo proteomic studies involving the cellular and molecular effects of cannabis and cannabis-derived compounds.

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“…Accumulated evidence reveals that the multifaceted AD pathogenesis starts with the accumulation of Aβ oligomers, which directly impacts the mitochondrial function via various molecular pathways. This results in decreased mitochondrial membrane potential, uncoupling of mitochondrial electron transport chain, and reduced ATP production, which ultimately leads to mitochondrial dysfunction [8]. The damage to mitochondria results in an imbalance between the production of free radicals and the antioxidative defense mechanism, causing chronic oxidative stress and triggering chronic endoplasmic reticulum (ER) stress [9].…”

Section: Introductionmentioning

confidence: 99%

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

2021

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Vitamin K2, known for its antioxidative and anti-inflammatory properties, can act as a potent neuroprotective molecule. Despite its action against mitochondrial dysfunction, the mechanism underlying the links between the protective effects of vitamin K2 and endoplasmic reticulum (ER) stress along with basal levels of total tau protein and amyloid-beta 42 (Aβ42) has not been elucidated yet. To understand the neuroprotective effect of vitamin K2 during metabolic complications, SH-SY5Y cells were treated with streptozotocin for 24 h and menadione for 2 h in a dose-dependent manner, followed by post-treatment of vitamin K2 for 5 h. The modulating effects of vitamin K2 on cell viability, lactate dehydrogenase release, reactive oxygen species (ROS), mitochondrial membrane potential, ER stress marker (CHOP), an indicator of unfolded protein response (UPR), inositol requiring enzyme 1 (p-IRE1α), glycogen synthase kinase 3 (GSK3α/β), total tau and Aβ42 were studied. Results showed that vitamin K2 significantly reduces neuronal cell death by inhibiting cytotoxicity and ROS levels and helps in the retainment of mitochondrial membrane potential. Moreover, vitamin K2 significantly decreased the expression of CHOP protein along with the levels and the nuclear localization of p-IRE1 α, thus showing its significant role in inhibiting chronic ER stress-mediated UPR and eventually cell death. In addition, vitamin K2 significantly down-regulated the expression of GSK3 α/β together with the levels of total tau protein, with a petite effect on secreted Aβ42 levels. These results suggested that vitamin K2 alleviated mitochondrial damage, ER stress and tauopathy-mediated neuronal cell death, which highlights its role as new antioxidative therapeutics targeting related cellular processes.

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Mitochondrial dysfunction in Alzheimer’s disease - a proteomics perspective

Cited by 35 publications

References 106 publications

Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

A Proteomic View of Cellular and Molecular Effects of Cannabis

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

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