Impaired spatial navigation and age‐dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice

Al‐Onaizi, Mohammed; Al‐Sarraf, Ahmad; Braysh, Kawthar; Kazem, Fatema; Al‐Hussaini, Heba; Rao, Muddanna S.; Narayana, K.; ElAli, Ayman

doi:10.1111/ejn.15835

Cited by 7 publications

(5 citation statements)

References 128 publications

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“…We recognize that although we have contextualized the findings of our metabolomic study in terms of cognitive decline and dementia, the study does not include cognitive function assessments. However, others utilizing the same models at a similar age to the mice in our study have demonstrated cognitive dysfunction [19,20], providing evidence that the db/db model is an appropriate model for T2DM-induced cognitive decline. In addition, while our study characterized the metabolome of the whole brain, there may be region-specific changes induced by T2DM that may be further modified by sex.…”

Section: Study Limitationssupporting

confidence: 67%

“…We selected 18 weeks of age (4.5 months) for our terminal timepoint. Others have shown that db / db mice will exhibit poorer performance on cognitive tests by this time frame (3–5 months of age) as compared to WT mice [ 19 ]. A flowchart of the experimental procedures can be found in Figure S1 .…”

Section: Methodsmentioning

confidence: 99%

“…In these mice, hyperinsulinemia is seen starting at approximately 2 weeks of age, obesity at 3–4 weeks of age, and hyperglycemia at 4–8 weeks of age [ 18 ]. In addition, adult db / db mice exhibit cognitive dysfunction at 3–5 months of age [ 19 , 20 ]. Therefore, the db / db mouse model is suitable for investigating the impact of T2DM on the brain metabolome.…”

Section: Introductionmentioning

confidence: 99%

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Sex Modifies the Impact of Type 2 Diabetes Mellitus on the Murine Whole Brain Metabolome

Norman,

Nuthikattu,

Milenkovic

et al. 2023

Metabolites

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Type 2 diabetes mellitus (T2DM) leads to the development of cardiovascular diseases, cognitive impairment, and dementia. There are sex differences in the presentation of T2DM and its associated complications. We sought to determine the impact of sex and T2DM on the brain metabolome to gain insights into the underlying mechanisms of T2DM-associated cognitive complications. Untargeted metabolomic analysis was performed, using liquid chromatography-mass spectrometry, on whole brain tissue from adult male and female db/db mice (a T2DM model) compared to wild-type (WT) C57Bl6/J mice. Regardless of sex, T2DM increased free fatty acids and decreased acylcarnitines in the brain. Sex impacted the number (103 versus 65 in males and females, respectively), and types of metabolites shifted by T2DM. Many choline-containing phospholipids were decreased by T2DM in males. Female-specific T2DM effects included changes in neuromodulatory metabolites (γ-aminobutyric acid, 2-linoleoyl glycerol, N-methylaspartic acid, and taurine). Further, there were more significantly different metabolites between sexes in the T2DM condition as compared to the WT controls (54 vs. 15 in T2DM and WT, respectively). T2DM alters the murine brain metabolome in both sex-independent and sex-dependent manners. This work extends our understanding of brain metabolic sex differences in T2DM, cognitive implications, and potential sex-specific metabolic therapeutic targets.

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Section: Study Limitationssupporting

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sex Modifies the Impact of Type 2 Diabetes Mellitus on the Murine Whole Brain Metabolome

Norman,

Nuthikattu,

Milenkovic

et al. 2023

Metabolites

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“…Because of a persistent loop of mutual activation between astrocytes and microglia, subsequently influencing neuronal activity and memory, it is likely that ACN inhibition might be sufficient to interrupt such a vicious cycle, preserving neuronal function. Reduced neuroinflammation can be, indeed, positively associated with the preservation of cognitive abilities we observed both in the AβO-induced and in indACNKO-AD mice, because of the strong association described between glial activation, neuroinflammation, and synaptic plasticity and memory (Al-Onaizi et al, 2022;Amirahmadi et al, 2022;Balducci et al, 2017;Hong et al, 2016;Morris et al, 2013;Sandhu et al, 2022;Zhang et al, 2022).…”

Section: Astroglial Can As a Central Hub Of Neuroinflammation And Hom...supporting

confidence: 60%

Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease

Tapella,

Dematteis,

La Vitola

et al. 2024

Glia

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Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell‐target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD‐related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN‐KO). In the former, we evaluated the ability of β‐amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN‐KO mice. Next, we generated a tamoxifen‐inducible astrocyte‐specific CaNB1 knock‐out in 3xTg‐AD mice (indACNKO‐AD). CaNB1 was deleted, by tamoxifen injection, in 11.7‐month‐old 3xTg‐AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β‐amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2‐month‐old wild type mice impaired recognition memory and fostered a pro‐inflammatory microglia phenotype, whereas in ACN‐KO mice, AβOs were inactive. In indACNKO‐AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte‐specific CaNB1 deletion is beneficial for both the abolishment of AβO‐mediated detrimental effects and treatment of ongoing AD‐related pathology, hence representing an intriguing target for AD therapy.

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“…Mouse cytokine antibody array (Abcam, Cat# ab133995) was used to evaluate the levels of 62 different cytokines in serum samples 23 . 4 samples from Control and LED treated group from both 420 nm & 450nm were used.…”

Section: Cytokine Antibody Arraymentioning

confidence: 99%

Exposure to short wavelength light absorbed by mitochondria is associated with weight gain, shifts in cytokine expression and anxiety-like behaviours.

Al-Hussaini,

Al-Onaizi,

Abed

et al. 2024

Preprint

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Mitochondria absorb short wavelengths around 420nm. This is associated with reduced ATP and restricted mobility. The 420-450nm range is a significant element of LED lighting and computer monitors. Here we expose freely moving mice to 420nm or 450nm lighting and show rapidly weight gain within a week. This may be due to reduced mitochondrial demand for circulating carbohydrates. Both groups displayed marked shifts in serum cytokines. Open field mobility was examined. The distance travelled was similar between both experimental groups and their controls. However, both experimental groups showed avoidance of central regions consistent with anxiety-like behaviours. This was significant in the 420nm group whose wavelength exposure is closer to peak mitochondrial absorbance. These data demonstrate the potential hazards of exposure to specific short wavelengths in the visual range now common in the built environment. Data are consistent with a wider literature on systemic problems arising from exposure to short wavelength light.

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Impaired spatial navigation and age‐dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice

Cited by 7 publications

References 128 publications

Sex Modifies the Impact of Type 2 Diabetes Mellitus on the Murine Whole Brain Metabolome

Sex Modifies the Impact of Type 2 Diabetes Mellitus on the Murine Whole Brain Metabolome

Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease

Exposure to short wavelength light absorbed by mitochondria is associated with weight gain, shifts in cytokine expression and anxiety-like behaviours.

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