Hyperglycemia induces RAGE-dependent hippocampal spatial memory impairments

Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease

“…In this model, blocking RAGE inhibits neuroinflammation and neurodegeneration markers (Gasparotto et al, 2018). Similar findings indicating that RAGE antagonist or RAGE knockout mice fail to present spatial memory deficits suggest that AGES play a role in cognitive impairment (Cai et al, 2016;Pugazhenthi et al, 2017;Momeni et al, 2021).…”

Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C‐terminal AAs 2‐5 to mitogen‐activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3‐MKK3‐p38 module assembly

“…Over‐expression of RAGE has been shown to activate p38MAPK and NF‐κB signaling in the brains of diabetic mice, which may lead to neuronopathies and neuroinflammation, and ultimately cognitive dysfunction (Gorska‐Ciebiada et al, 2015 ; Zhao et al, 2018 ; Zhu et al, 2020 ). Hyperglycemia is linked to the formation of AGEs and the generation of reactive oxygen species (ROS), both of which are considered as major contributors to the development of cognitive deficits of diabetes (Momeni et al, 2021b ). Interactions between AGEs and RAGE give rise to a cascade of events that triggers sustained activation of p38MAPK and NF‐κB signaling pathway, and further upregulation of RAGE and ROS production, ultimately leading to diabetes‐induced neurological complications (Momeni et al, 2021a ; Tan et al, 2015 ).…”

“…The cytoplasmic domain of RAGE is critical for RAGE‐dependent downstream MAPK signal activation, which ultimately leads to cellular damage (Jules et al, 2013 ). Inhibition or knockout of RAGE in the brain is accompanied by a reduction in neuronal damage and synaptic dysfunction, and an improvement in behavioral deficits in a mouse model of diabetes and neurodegenerative disease (Momeni et al, 2021b ; Toth et al, 2007 ; Wang et al, 2018 ) indicated that RAGE may be a potential therapeutic target for DE. Nevertheless, the precise molecular mechanism by which RAGE regulates the p38MAPK pathway remains elusive.…”

The molecular mechanism underlying mitophagy‐mediated hippocampal neuron apoptosis in diabetes‐related depression

“…Current studies have found that enhanced mitophagy and mitochondrial dysfunction resulted in deficient ATP production, an increased mitochondrial reactive oxygen species (ROS), a release of superfluous cytochrome c (Cyt‐c), up‐regulation of Bax, caspase‐3 and caspase‐9, and further an initiation of endogenous apoptosis pathways 42,43 . Further evidence also indicated that hyperglycaemia‐induced RAGE signalling altered glutamate AMPA receptor function and expression, result in an elevated glutamate levels and an increase in cytosolic reactive oxygen species (ROS), caused hippocampal neuron apoptosis and eventually led to neurotransmitter dopamine deficiency and synaptic transmission impairment 39,44 . Hence, we proposed a new hypothesis that aberrant Glu‐GluR2‐Parkin pathway led to mitophagy‐mediated hippocampal neuron apoptosis in diabetes‐related depression.…”

“…42,43 Further evidence also indicated that hyperglycaemiainduced RAGE signalling altered glutamate AMPA receptor function and expression, result in an elevated glutamate levels and an increase in cytosolic reactive oxygen species (ROS), caused hippocampal neuron apoptosis and eventually led to neurotransmitter dopamine deficiency and synaptic transmission impairment. 39,44 Hence, we proposed a new hypothesis that aberrant Glu-GluR2-Parkin pathway led to mitophagy-mediated hippocampal neuron apoptosis in diabetes-related depression. in simulated DD conditions.…”