Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

Haddad, Mohamed; Perrotte, Morgane; Khedher, Mohamed Raâfet Ben; Demongin, Clément; Lepage, Aurélie; Fülöp, Tamás; Ramassamy, Charles

doi:10.3390/ijms20194906

Cited by 33 publications

(33 citation statements)

References 98 publications

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“…Methylglyoxal in serum distinguishes MCI from controls but not from AD. Meanwhile, serum glyoxal levels differentiate MCI from control and AD groups [35]. The levels of carboxymethylysine in serum correlate negatively with the clinical cognitive as measured by MMSE [34].…”

Section: Discussionmentioning

confidence: 97%

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Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Gibson

Luchsinger

Cirio

et al. 2020

JAD

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Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

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Section: Discussionmentioning

confidence: 97%

“…Thus, AGE may be a promising therapeutic target to prevent or delay the progression of AD [35]. Numerous studies in patients with diabetes show that benfotiamine diminishes AGE [21].…”

Section: Introductionmentioning

confidence: 99%

Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Gibson

Luchsinger

Cirio

et al. 2020

JAD

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“…Among all oxidative stress mediators, GLO-1 plays an important role (23). GLO-1 is an enzyme that detoxi es MG. MG is an effective precursor of advanced glycation end products and is considered to be a key factor in neuronal injury (24,25). DEX administration halts AD progression in APP/PS1 mice, it may be through regulating GLO-1.…”

Section: Dex Treatment Increases Sod Gsh and Decreases Mda Levels In Neurons Exposed To Aβmentioning

confidence: 99%

Dexmedetomidine Attenuates Hippocampal Damage and Improves Cognition by Up-Regulating Glyoxalase1 in APP/PS1 Mice

Guo¹,

Zhang²,

Gao³

et al. 2021

Preprint

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Background: Dexmedetomidine (DEX), an α2-adrenoceptor agonist, has been reported to possess neuroprotective effects against postoperative cognitive impairment. GLO-1 plays a key role in the pathogenesis of Alzheimer’s disease (AD). Here, the primary goal was to assess whether DEX affect GLO-1 and protect cognition impairment in APP/PS1 transgenic mice.Methods: After DEX was intraperitoneally injected in APP/PS1 mice, behavior was tested by Water Maze to illustrate whether DEX treatment has a significantly positive effect on ameliorating the cognition deficits in AD. We assessed the effect of DEX on the expression of GLO-1 and the production of other oxidative stress factors by ELISA and Western blot. To determine whether DEX play roles in the Aβ induced neuron apoptosis, flow cytometry was used.Results: DEX treatment significantly ameliorated cognition deficits in APP/PS1 mice. DEX increased GLO-1 expression and decreased MG activity in the hippocampus. In addition, DEX increased activity of SOD, GSH and reduced the activity of MDA. In vitro, DEX could protect the neuron apoptosis induced by Aβ. GLO-1 inhibitor could block the protective role of DEX.Conclusion: Taken together, our findings suggest that DEX prevents progression of AD-like pathology through upregulating GLO-1.

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“…The copyright holder for this preprint (which this version posted May 11, 2021. ; https://doi.org/10.1101/2021.05.10.443439 doi: bioRxiv preprint Griggs et al 4 altered AIS geometry in animal models, including type 2 diabetes (Andersen et al, 2018), Alzheimer's disease (Kuhla et al, 2007;Haddad et al, 2019), aging (Kuhla et al, 2006;Beeri et al, 2011;Srikanth et al, 2013), multiple sclerosis (Wetzels et al, 2019), and pain (Düll et al, 2019). The effect of methylglyoxal, glucose, or insulin on AIS geometry and the operation of neuronal networks is unknown.…”

Section: Introductionmentioning

confidence: 99%

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Griggs

et al. 2021

Preprint

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Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or position along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. The key type 2 diabetes-related factor that alters AIS geometry is unknown. Here, we tested whether modifying the levels of insulin, glucose, or methylglyoxal, a reactive carbonyl species that is a metabolite of glucose, changes AIS geometry in mature cultures of dissociated postnatal mouse cortex using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification appreciably altered AIS length. Elevation of methylglyoxal produced reversible AIS shortening without cell death. Multi-electrode array recordings revealed a biphasic effect of methylglyoxal on neuronal network activity: an immediate, transient ~300% increase in spiking and bursting rates was followed by a ~20% reduction from baseline at 3 h. AIS length was unchanged at 0.5 h or 3 h after adding methylglyoxal, whereas development of AIS shortening at 24 h was associated with restoration of spiking to baseline levels. Immunostaining for the excitatory neuron marker Ca2+/calmodulin-dependent protein kinase II alpha revealed AIS shortening in both excitatory and inhibitory neuron populations. This suggests that complex mechanisms maintain neuronal network operation after acute exposure to the disease metabolite methylglyoxal. Importantly, our results indicate that methylglyoxal could be a key mediator of AIS shortening during type 2 diabetes.

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Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

Cited by 33 publications

References 98 publications

Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Dexmedetomidine Attenuates Hippocampal Damage and Improves Cognition by Up-Regulating Glyoxalase1 in APP/PS1 Mice

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

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