Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches

Mary, Arnaud; Eysert, Fanny; Checler, Frédéric; Chami, Mounia

doi:10.1038/s41380-022-01631-6

Cited by 75 publications

(72 citation statements)

References 115 publications

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“…According to the mitochondrial cascade hypothesis, these organelles are suggested to mediate or possibly even initiate pathological molecular cascades in AD. It has been reported that GIIA expression is increased in affected tissues [ 8 ] and that nerve cell death is preceded by the degeneration of the mitochondria [ 11 ]. Similar mitochondrial degeneration was reported when the nerve cells were exposed to snake venom β-neurotoxic GIIAs [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…GIIA secreted by reactive astrocytes around the amyloid plaques in an AD brain has been shown to regulate the processing of the amyloid precursor protein in neuronal cells [ 9 , 10 ]; however, no other clear evidence about the involvement of GIIA in AD is currently available. Mitochondrial dysfunctions are central players in AD [ 11 ]. In AD brains, the mitochondria degenerate, as they do when nerve cells are intoxicated by the presynaptic neurotoxic snake venom sPLA 2 s (β-neurotoxins).…”

Section: Introductionmentioning

confidence: 99%

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Rat Group IIA Secreted Phospholipase A2 Binds to Cytochrome c Oxidase and Inhibits Its Activity: A Possible Episode in the Development of Alzheimer’s Disease

Ivanušec

Šribar

Leonardi

et al. 2022

IJMS

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Alzheimer’s disease (AD), a progressive form of dementia, is characterized by the increased expression of secreted phospholipase A2 group IIA (GIIA) in the affected tissue and the dysfunction of neuronal mitochondria, similar to that induced by an orthologous GIIA from snake venom, β-neurotoxic ammodytoxin (Atx), in the motor neurons. To advance our knowledge about the role of GIIA in AD, we studied the effect of rat GIIA on the neuronal mitochondria and compared it with that of the Atx. We produced recombinant rat GIIA (rGIIA) and its enzymatically inactive mutant, rGIIA(D49S), and demonstrated that they interact with the subunit II of cytochrome c oxidase (CCOX-II) as Atx. rGIIA and rGIIA(D49S) bound to this essential constituent of the respiratory chain complex with an approximately 100-fold lower affinity than Atx; nevertheless, both rGIIA molecules potently inhibited the CCOX activity in the isolated rat mitochondria. Like Atx, rGIIA was able to reach the mitochondria in the PC12 cells from the extracellular space, independent of its enzymatic activity. Consistently, the inhibition of the CCOX activity in the intact PC12 cells and in the rat’s brain tissue sections was clearly demonstrated using rGIIA(D49S). Our results show that the effects of mammalian and snake venom β-neurotoxic GIIA on the neuronal mitochondria have similar molecular backgrounds. They suggest that the elevated extracellular concentration of GIIA in the AD tissue drives the translocation of this enzyme into local neurons and their mitochondria to inhibit the activity of the CCOX in the respiratory chain. Consequently, the process of oxidative phosphorylation in the neurons is attenuated, eventually leading to their degeneration. Atx was thus revealed as a valuable molecular tool for further investigations of the role of GIIA in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rat Group IIA Secreted Phospholipase A2 Binds to Cytochrome c Oxidase and Inhibits Its Activity: A Possible Episode in the Development of Alzheimer’s Disease

Ivanušec

Šribar

Leonardi

et al. 2022

IJMS

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“…Changes in mitophagy have been reported to lead to a gradual accumulation of defective mitochondria in AD [107]. In detail, an unbalanced increase in ROS levels occurs under AD conditions, together with a lowering of antioxidant mechanisms, which eventually causes OS.…”

Section: Defective Mitophagy In Admentioning

confidence: 99%

Therapeutic Potential of Targeting Mitochondria for Alzheimer’s Disease Treatment

Atlante

Amadoro

Latina

et al. 2022

JCM

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Alzheimer’s disease (AD), a chronic and progressive neurodegenerative disease, is characterized by memory and cognitive impairment and by the accumulation in the brain of abnormal proteins, more precisely beta-amyloid (β-amyloid or Aβ) and Tau proteins. Studies aimed at researching pharmacological treatments against AD have focused precisely on molecules capable, in one way or another, of preventing/eliminating the accumulations of the aforementioned proteins. Unfortunately, more than 100 years after the discovery of the disease, there is still no effective therapy in modifying the biology behind AD and nipping the disease in the bud. This state of affairs has made neuroscientists suspicious, so much so that for several years the idea has gained ground that AD is not a direct neuropathological consequence taking place downstream of the deposition of the two toxic proteins, but rather a multifactorial disease, including mitochondrial dysfunction as an early event in the pathogenesis of AD, occurring even before clinical symptoms. This is the reason why the search for pharmacological agents capable of normalizing the functioning of these subcellular organelles of vital importance for nerve cells is certainly to be considered a promising approach to the design of effective neuroprotective drugs aimed at preserving this organelle to arrest or delay the progression of the disease. Here, our intent is to provide an updated overview of the mitochondrial alterations related to this disorder and of the therapeutic strategies (both natural and synthetic) targeting mitochondrial dysfunction.

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“…Aβ may induce mitochondrial dysfunction in AD in many ways ( Figure 8 ): (i) impairment of membranes and inhibition of mitochondrial enzymes, such as respiratory complexes, leading to decreased ATP production and increased ROS generation; inhibition of oxoglutarate dehydrogenase complex (OGDC, or α-ketoglutarate dehydrogenase complex), leading to changes in TCA; and interaction with 17β-hydroxysteroid dehydrogenase type 10 (HSD10, formerly known as Aβ binding alcohol dehydrogenase or ABAD), leading to enhancement of Aβ-induced cell stress [ 288 , 289 ]; (ii) increased expression of mitochondrial PPIF, leading to formation of PPIF-mPTP [ 224 , 290 ]; (iii) impairment of mitochondrial Ca 2+ buffering capacity, leading to calcium overload in the mitochondria, calcium-induced mPTP opening, inhibition of ATP production, increased ROS production, increased cytochrome c release, apoptosis, and neuronal injury; (iv) inhibition of preprotein import into mitochondria via the TIM/TOM complex [ 283 , 291 ]; (v) impairment of fusion/fission processes, mitophagy, and mitochondrial movement [ 292 ]; and (vi) decreased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which is a regulator of mitochondrial biogenesis [ 275 , 293 , 294 ].…”

Section: Linking the Amyloid Tau And The Mitochondrial Hypotheses Of ...mentioning

confidence: 99%

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Fišar

2022

Biomolecules

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Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

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Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches

Cited by 75 publications

References 115 publications

Rat Group IIA Secreted Phospholipase A2 Binds to Cytochrome c Oxidase and Inhibits Its Activity: A Possible Episode in the Development of Alzheimer’s Disease

Rat Group IIA Secreted Phospholipase A2 Binds to Cytochrome c Oxidase and Inhibits Its Activity: A Possible Episode in the Development of Alzheimer’s Disease

Therapeutic Potential of Targeting Mitochondria for Alzheimer’s Disease Treatment

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

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