Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer’s disease mouse model

Ferreiro, Elisabete; Lanzillo, Mariagrazia; Canhoto, Diogo; Silva, António M. Carvalho da; Mota, Sandra I.; Dias, Iněs; Ferreira, Ildete L.; Fontes, Ana; Mastrella, Giorgia; Pinheiro, Paulo S.; Valero, Jorge; Rego, A. Cristina

doi:10.1016/j.neurobiolaging.2020.04.003

Cited by 21 publications

(12 citation statements)

References 68 publications

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“…In addition, decreased FC between the dAI and hippocampus was negatively correlated with the HbA1c level, suggesting that chronic high glucose may damage the dAI and the hippocampal pathway. Animal research ( Ferreiro et al, 2020 ) has confirmed that chronic hyperglycemia can damage hippocampal neurons and memory function, and another study showed that high glucose is associated with abnormal memory in patients with T2DM ( Zhang et al, 2015 ). Therefore, it is plausible to speculate that hyperglycemia may affect memory function by disrupting the dAI and the hippocampal pathway.…”

Section: Discussionmentioning

confidence: 99%

Altered Functional Connectivity of Insular Subregions in Type 2 Diabetes Mellitus

et al. 2021

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Diabetes-related brain damage can lead to cognitive decline and increase the risk of depression, but the neuropathological mechanism of this phenomenon remains unclear. Different insular subregions have obvious functional heterogeneity, which is related to many aspects of type 2 diabetes mellitus (T2DM)-related brain damage. However, little is known about changes in functional connectivity (FC) in insular subregions in patients with T2DM. Therefore, we aimed to investigate FC between different insular subregions and clinical/cognitive variables in patients with T2DM. Fifty-seven patients with T2DM and 55 healthy controls (HCs) underwent a neuropsychological assessment and resting-state FC examination. We defined three insular subregions, including the bilateral dorsal anterior insula (dAI), bilateral ventral anterior insula (vAI), and bilateral posterior insula (PI). We examined differences in FC between insular subregions and the whole brain in patients with T2DM compared with HCs. A correlation analysis was performed to examine the relationship between FC and clinical/cognitive variables. Compared with HCs, patients with T2DM showed significantly decreased FC between the dAI and the right inferior frontal gyrus, right superior/middle temporal gyrus, right hippocampus, and right precentral gyrus. FC between the vAI and the right supramarginal gyrus, as well as the PI and the right precentral/postcentral gyrus, was reduced in the T2DM group compared with the control group. In the T2DM group, we showed a significant negative correlation between glycated hemoglobin concentration and FC in the dAI and right hippocampus (r = −0.428, P = 0.001) after Bonferroni correction. We conclude that different insular subregions present distinct FC patterns with functional regions and that abnormal FC in these insular subregions may affect cognitive, emotional, and sensorimotor functions in patients with T2DM.

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Section: Discussionmentioning

confidence: 99%

Altered Functional Connectivity of Insular Subregions in Type 2 Diabetes Mellitus

et al. 2021

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“…Cavalieri’s method has been deeply revised, and it is considered the gold standard method for volume estimations. However, the TCS method is less extended; and, to our knowledge, we have been the only ones applying it for volume estimations in neuroscience papers [28, 29]. To be able to compare and validate the new method, we have generated four artificial objects with different morphologies and known volumes ( Table 2 and Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

VolumesJ: A new method and tool for volumetric estimation of brain structures after serial sectioning

Ferreiro

Rodríguez-Iglesias

Cardoso

et al. 2022

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Volume estimations are crucial for many neuroscience studies, allowing the evaluation of changes in the size of brain areas that may have relevant functional consequences. Classical histological methods and modern human brain imaging techniques rely on obtaining physical or digital sections, with a known thickness, of the organ to be analyzed. This "slicing" strategy is associated with an ineludible loss of information about the three-dimensional organization of the analyzed structures, especially affecting the precision of volumetric measurements. To overcome this problem, several methods have been developed. One of the most commonly used approaches for volume estimation is the classical Cavalieri's method. Within this book chapter, we provide first an overview of Cavalieri's method and propose a new one, named the Truncated Cone Shape method, for the estimation of volumes from tissue sections. Second, we compare the accuracy of both methods using computer-generated objects of different shapes and sizes. We conclude that, more frequently, the TCS method provides a better estimate of real volumes than Cavalieri's method. And third, we describe a protocol to estimate volumes using a self-developed and freely available tool for ImageJ: VolumestJ. This new tool helps to implement both Cavalieri's and TCS methods using digital images of tissue sections. We consider that VolumestJ will facilitate the labor of researchers interested in volume estimations.

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“…Relevant fractions were evaporated to dryness to obtain an oil that was triturated with methanol to afford the title compound as a white solid (70 mg, 83%). 1 N-Boc-γ-L-Glz[-L-Glp(4-thio)-Gly-OtBu]-OtBu (11). Under argon, carbonyl diimidazole (112 mg, 0.69 mmol) was added to a solution of 8 (300 mg, 0.58 mmol) in dioxane (4 mL), and the resulting mixture was stirred at rt overnight.…”

Section: Nh 2 -γ-L-glz[-l-cys(sac)-gly-oh]-oh (1)mentioning

confidence: 99%

“…It is associated with poor cognition. Empirically, it is a risk factor for Alzheimer’s and related dementias. , Insufficient ability to regulate blood glucose (glucose intolerance) is associated with the accumulation of pathologic β-amyloid plaques, neuroinflammation, oxidative stress, mitochondrial dysfunction, and ultimately neurodegeneration. Immunohistochemistry of senile plaques and neurofibrillary tangles show overabundance of AGEs in human and animal brain. , Glycation of Aβ1–42 enhances its toxicity and tendency to aggregate .…”

Section: Introductionmentioning

confidence: 99%

Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer’s Disease

et al. 2022

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Addressing glycation-induced oxidative stress in Alzheimer's disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group. In vitro and in vivo stability studies identified promising prodrugs that could deliver pharmacologically relevant brain levels of ψ-GSH. When administered orally to a mouse model generated by the intracerebroventricular injection of Aβ1−42, the compounds conferred cognitive benefits. Biochemical and histological examination confirmed their effects on neuroinflammation and oxidative stress. Collectively, we have identified orally efficacious prodrugs of ψ-GSH that are able to restore brain glyoxalase activity and mitigate inflammatory and oxidative pathology associated with AD.

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Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer’s disease mouse model

Cited by 21 publications

References 68 publications

Altered Functional Connectivity of Insular Subregions in Type 2 Diabetes Mellitus

Altered Functional Connectivity of Insular Subregions in Type 2 Diabetes Mellitus

VolumesJ: A new method and tool for volumetric estimation of brain structures after serial sectioning

Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer’s Disease

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