Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease

Wilkins, Heather; Swerdlow, Russell H.

doi:10.2174/1568026615666150827095102

Cited by 98 publications

(57 citation statements)

References 81 publications

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“…Energetic and mitochondrial dysfunction may contribute to neuroinflammation, which in turn could cause mitochondrial dysfunction [10]. Neuroinflammation can be revealed in isolated glia from AD mice [5,11].…”

Section: Introductionmentioning

confidence: 99%

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Gijsel-Bonnello¹,

Baranger²,

Benech³

et al. 2017

PLoS ONE

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Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer’s disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

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Section: Introductionmentioning

confidence: 99%

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Gijsel-Bonnello¹,

Baranger²,

Benech³

et al. 2017

PLoS ONE

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“…Moreover, it is increasingly that mitochondrial dysfunction and neuroinflammation are interdependent lesions in AD. The direct or indirect manipulation of mitochondria through interfering with bioenergetic pathways could reduce neuroinflammation in AD [51]. Therefore, the correlation of elevated mRNA level of PGC1-α with mitochondrial biogenesis, and their relationship with neuroinflammation should be further studied using the current model.…”

Section: Discussionmentioning

confidence: 99%

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

Liu

Chu

Yan

et al. 2020

J Neuroinflammation

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Background: Both human and animal studies have shown beneficial effects of physical exercise on brain health but most tend to be based on aerobic rather than resistance type regimes. Resistance exercise has the advantage of improving both muscular and cardiovascular function, both of which can benefit the frail and the elderly. However, the neuroprotective effects of resistance training in cognitive impairment are not well characterized. Methods: We evaluated whether short-term resistant training could improve cognitive function and pathological changes in mice with pre-existing cognitive impairment. Nine-month-old 3xTg mouse underwent a resistance training protocol of climbing up a 1-m ladder with a progressively heavier weight loading. Results: Compared with sedentary counterparts, resistance training improved cognitive performance and reduced neuropathological and neuroinflammatory changes in the frontal cortex and hippocampus of mice. In line with these results, inhibition of pro-inflammatory intracellular pathways was also demonstrated. Conclusions: Short-term resistance training improved cognitive function in 3xTg mice, and conferred beneficial effects on neuroinflammation, amyloid and tau pathology, as well as synaptic plasticity. Resistance training may represent an alternative exercise strategy for delaying disease progression in Alzheimer's disease.

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“…Another target for primary anti-AD strategies is the manipulation of the bioenergetic pathways (Wilkins & Swerdlow, 2016) and/or factors that regulate apoptosis (Shimohama, 2000). AD is strongly associated with mitochondrial dysfunction (Correia et al, 2013).…”

Section: Effects Of Gammapyrone On the Mitochondrial Functioning Anmentioning

confidence: 99%

“…AD is strongly associated with mitochondrial dysfunction (Correia et al, 2013). The relationship between mitochondrial impairment and neuroinflammation are still unknown, although it has been reported that these phenomena influence each other (Wilkins & Swerdlow, 2016). Mitochondria are an essential target that regulates protein synthesis and synapse remodeling (Devine & Kittler, 2018).…”

Section: Effects Of Gammapyrone On the Mitochondrial Functioning Anmentioning

confidence: 99%

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

Piļipenko

Narbute

Amara

et al. 2019

J of Neuroscience Research

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Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer’s disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma‐aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: “free” moiety attached to the position 4 of the 1,4‐dihydropyridine (DHP) ring, and two “crypto” moieties as part of the DHP scaffold. The “free” and “crypto” GABA moieties are linked by a peptide bond (–CONH–), resulting in a peptide‐mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di‐2‐ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA‐A and GABA‐B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide‐like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti‐dementia drugs.

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Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease

Cited by 98 publications

References 81 publications

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

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