SummaryThere is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD‐like model mice on high‐AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle‐linked disease epidemic.
Type 2 diabetes (T2D) is associated with increased risk of Alzheimer's disease (AD). There is evidence for impaired blood–brain barrier (BBB) in both diseases, but its role in the interplay between them is not clear. Here, we investigated the effects of high‐fat diet (HFD), a model for T2D, on the Tg2576 mouse model of AD, in regard to BBB function. We showed that HFD mice had higher weight, more insulin resistance, and higher serum HDL cholesterol levels, primarily in Tg2576 mice, which also had higher brain lipids content. In terms of behavior, Tg2576 HFD mice were less active and more anxious, but had better learning in the Morris Water Maze compared to Tg2576 on regular diet. HFD had no effect on the level of amyloid beta 1–42 in the cortex of Tg2576 mice, but increased the transcription level of insulin receptor in the hippocampus. Tg2576 mice on regular diet demonstrated more BBB disruption at 8 and 12 months accompanied by larger lateral ventricles volume in contrast to Tg2576 HFD mice, whose BBB leakage and ventricular volume were similar to wild‐type (WT) mice. Our results suggest that in AD, HFD may promote better cognitive function through improvements of BBB function and of brain atrophy but not of amyloid beta levels. Lipid metabolism in the CNS and peripheral tissues and brain insulin signaling may underlie this protection.
Disruption of brain insulin signaling may explain the higher Alzheimer's disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-months intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin+exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15-30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.
Cognitive deficits, especially memory loss, are common and devastating neuropsychiatric sequelae of traumatic brain injury (TBI). The deficits may persist for years and may be accompanied by increased risk of developing early- onset dementia. Past attempts to reverse the neuropathological effects of brain injury with glutamate-N-methyl-d-aspartate (NMDA) antagonists failed to show any benefits or worsened the outcome, suggesting that activation, rather than blockage, of the NMDA receptor (NMDAR) may be useful in the subacute period after TBI and stroke. Activation of the NMDAR requires occupation of the glycine-modulatory site by co-agonists to achieve its synaptic functions. Glycine and d-serine are endogenous ligands/co-agonists of synaptic NMDARs in many areas of the mature brain. The aim of the present study was to evaluate the effect of 6-chlorobenzo(d)isoxazol-3-ol (CBIO), an inhibitor of D-amino acid oxidase (DAAO), which degrades d-serine, on cognitive outcome in a mouse model of TBI. Because treating TBI animals with CBIO elevates the endogenous levels of d-serine, we compared this novel treatment with treatment by exogenous d-serine alone and combined with CBIO. The results show that a single treatment (24 h post-injury) with CBIO in the mouse model of closed head injury significantly improves cognitive and motor function, and decreases lesion volume and the inflammatory response. Moreover, the compound proved to be neuroprotective, as the hippocampal volume and the number of neurons in hippocampal regions increased. Treatment with CBIO boosted the NR1 and phospho- NR1 subunits of the NMDAR and affected the CREB, phospho-CREB, and brain-derived neurotropic factor (BDNF) pathways. These findings render CBIO a promising, novel treatment for cognitive impairment following TBI.
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