The Methylglyoxal/RAGE/NOX-2 Pathway is Persistently Activated in the Hippocampus of Rats with STZ-Induced Sporadic Alzheimer’s Disease

Moreira, Ana Paula; Vizuete, Adriana Fernanda Kuckartz; Zin, Lisandra Eda Fusinato; Marques, Charlanne Oliveira de; Pacheco, Rafaela Ferreira; Leal, Miriara B; Gonçalves, Carlos‐Alberto

doi:10.1007/s12640-022-00476-9

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…Interestingly, we could not confirm an increased RAGE expression in one-year-old S100Btg mice. In neurodegenerative diseases, such as AD, RAGE upregulation has been implicated in the stimulation of neuronal APP expression (e.g., [ 55 ]), and APP has been demonstrated to induce microglial activation accompanied by an increased inducible NO synthase expression [ 56 ]. We did not find any effect of long-term increased S100B levels on APP expression in one-year-old S100Btg mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Longterm Increased S100B Enhances Hippocampal Progenitor Cell Proliferation in a Transgenic Mouse Model

Rodrigues

Wartchow

Buchfelder

et al. 2022

IJMS

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(1) The neurotrophic protein S100B is a marker of brain injury and has been associated with neuroregeneration. In S100Btg mice rendering 12 copies of the murine S100B gene we evaluated whether S100B may serve as a treatment option. (2) In juvenile, adult, and one-year-old S100Btg mice (female and male; n = 8 per group), progenitor cell proliferation was quantified in the subgranular zone (SGZ) and the granular cell layer (GCL) of the dentate gyrus with the proliferative marker Ki67 and BrdU (50 mg/kg). Concomitant signaling was quantified utilizing glial fibrillary acidic protein (GFAP), apolipoprotein E (ApoE), brain-derived neurotrophic factor (BDNF), and the receptor for advanced glycation end products (RAGE) immunohistochemistry. (3) Progenitor cell proliferation in the SGZ and migration to the GCL was enhanced. Hippocampal GFAP was reduced in one-year-old S100Btg mice. ApoE in the hippocampus and frontal cortex of male and BDNF in the frontal cortex of female S100Btg mice was reduced. RAGE was not affected. (4) Enhanced hippocampal neurogenesis in S100Btg mice was not accompanied by reactive astrogliosis. Sex- and brain region-specific variations of ApoE and BDNF require further elucidations. Our data reinforce the importance of this S100Btg model in evaluating the role of S100B in neuroregenerative medicine.

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Section: Discussionmentioning

confidence: 99%

Longterm Increased S100B Enhances Hippocampal Progenitor Cell Proliferation in a Transgenic Mouse Model

Rodrigues

Wartchow

Buchfelder

et al. 2022

IJMS

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“…Older mice have elevated MG-AGEs in their cerebral cortices and hippocampi, leading to mitochondrial dysfunction . This observation was recapitulated in rats with streptozotocin-induced AD, which exhibited persistent activation of the MG/AGE/RAGE/NOX-2 pathway . Transgenic mouse models mimicking AD have increased expression and activation of RAGE in astrocytes, particularly those in the hippocampus, a key memory controller .…”

Section: Physiological Impact Of Mg and Mg-agesmentioning

confidence: 92%

Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

Lai

Gonzalez

Zoukari

et al. 2022

Chem. Res. Toxicol.

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Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant electrophile formed from lipid, protein, and glucose metabolism at intracellular levels of 1–4 μM. MG covalently modifies DNA, RNA, and protein, forming advanced glycation end products (MG-AGEs). MG and MG-AGEs are associated with the onset and progression of many pathologies including diabetes, cancer, and liver and kidney disease. Regulating MG and MG-AGEs is a potential strategy to prevent disease, and they may also have utility as biomarkers to predict disease risk, onset, and progression. Here, we review recent advances and knowledge surrounding MG, including its production and elimination, mechanisms of MG-AGEs formation, the physiological impact of MG and MG-AGEs in disease onset and progression, and the latter in the context of its receptor RAGE. We also discuss methods for measuring MG and MG-AGEs and their clinical application as prognostic biomarkers to allow for early detection and intervention prior to disease onset. Finally, we consider relevant clinical applications and current therapeutic strategies aimed at targeting MG, MG-AGEs, and RAGE to ultimately improve patient outcomes.

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“…Moreover, in the same experimental model, CA pre-treatment (10 µM for 1 h) partially reduced the Aβ42/43-induced apoptosis by suppressing the activation of caspase activation pathways and reducing the presence of cleaved PARP [ 253 ]. As described above, MG is a potent precursor of AGEs and is closely associated with an increase of OS and inflammatory status in AD [ 254 , 255 ]. Interestingly, in SH-SY5Y cells, CA exhibits neuroprotection against MG-mediated neurotoxicity, directly activating the PI3K/Akt/Nrf2 signalling pathway [ 163 ].…”

Section: Neuroprotective Potential Of β-Caryophyllene and Carnosic Ac...mentioning

confidence: 99%

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

2022

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Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.

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The Methylglyoxal/RAGE/NOX-2 Pathway is Persistently Activated in the Hippocampus of Rats with STZ-Induced Sporadic Alzheimer’s Disease

Cited by 13 publications

References 48 publications

Longterm Increased S100B Enhances Hippocampal Progenitor Cell Proliferation in a Transgenic Mouse Model

Longterm Increased S100B Enhances Hippocampal Progenitor Cell Proliferation in a Transgenic Mouse Model

Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

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