Sexual dimorphism in the peripheral metabolic homeostasis and behavior in the <scp>TgF344‐AD</scp> rat model of Alzheimer's disease

Srivastava, Hemant; Lasher, Alexander Tate; Nagarajan, Akash; Sun, Liou Y.

doi:10.1111/acel.13854

Cited by 13 publications

(13 citation statements)

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“…Our finding that the TgF344‐AD rats in our study weighed more than WT controls is also not likely an artifact of the different vendors given that data from our colony and previously published research has shown that these rats weigh more than their WT littermates (Anckaerts et al, 2019; Srivastava et al, 2023). Our spontaneous alternation data and other published measures of activity (Cohen et al, 2013; Kelberman et al, 2022) do not suggest that these rats move less and expend less energy, although there is a report indicating that 6–12‐month‐old female but not male TgF344‐AD rats are hypoactive (Saré et al, 2020).…”

Section: Discussionsupporting

confidence: 56%

“…The more severe pathology in females could be because of possible harmful consequences of cyclical increases in follicle-stimulating hormone (FSH) (Xiong et al, 2022) or double dosing of x-linked chromosome products such as x-linked ubiquitin-specific peptidase 11 (Yan et al, 2022). These differences may also result from impaired glucose clearance and reduced insulin sensitivity reported in young female but not male TgF344-AD rats (Srivastava et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

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Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Anderson

Sharma

Kelberman

et al. 2023

Journal of Neurochemistry

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Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late‐life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344‐AD rats that overexpress mutant human amyloid precursor protein and presenilin‐1 and wild‐type (WT) controls to determine whether inducing obesity with a high‐fat/high‐sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up‐regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC‐dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long‐term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD‐induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD‐induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.image

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Anderson

Sharma

Kelberman

et al. 2023

Journal of Neurochemistry

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“…The Tg female animals had higher body weights than WT females at the termination of the study at both 8- and 12-months of age, while the Tg males had greater body weights than WT males at the 8-month of age study termination. These results are consistent with other studies that have reported increased body weights in female TgF344-AD compared to WT rats [ 22 , 23 ]. In contrast, increased body weight in the male TgF344-AD rats was transitory since no differences in weight between genotypes were observed at 12 months of age and this finding is consistent with other studies that found no difference in body weight between TGF344-AD and WT male animals [ 23 , 24 ].…”

Section: Discussionsupporting

confidence: 93%

The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats

Rutkowsky,

Roland,

Valenzuela

et al. 2024

Aging

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Studies suggest that ketogenic diets (KD) may improve memory in mouse models of aging and Alzheimer’s disease (AD). This study determined whether a continuous or intermittent KD (IKD) enhanced cognitive behavior in the TgF344-AD rat model of AD. At 6 months-old, TgF344-AD and wild-type (WT) littermates were placed on a control (CD), KD, or IKD (morning CD and afternoon KD) provided as two meals per day for 2 or 6 months. Cognitive and motor behavior and circulating β-hydroxybutyrate (BHB), AD biomarkers and blood lipids were assessed. Animals on a KD diet had elevated circulating BHB, with IKD levels intermediate to CD and KD. TgF344-AD rats displayed impaired spatial learning memory in the Barnes maze at 8 and 12 months of age and impaired motor coordination at 12 months of age. Neither KD nor IKD improved performance compared to CD. At 12 months of age, TgF344-AD animals had elevated blood lipids. IKD reduced lipids to WT levels with KD further reducing cholesterol below WT levels. This study shows that at 8 or 12 months of age, KD or IKD intervention did not improve measures of cognitive or motor behavior in TgF344-AD rats; however, both IKD and KD positively impacted circulating lipids.

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“…However, others investigating the mouse microbiome did not report any changes in diversity with age (Binyamin et al., 2020 ). Beta diversity changes and modulation of community structure with age have been reported in another mice study (Binyamin et al., 2020 ) and our earlier rat study (Nagarajan et al., 2023 ; Srivastava et al., 2023 ). This is further evidence that the gut microbiota changes significantly with age.…”

Section: Discussionsupporting

confidence: 77%

Long term methionine restriction: Influence on gut microbiome and metabolic characteristics

Nagarajan,

Lasher,

Morrow

et al. 2024

Aging Cell

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The Methionine restriction (MR) diet has been shown to delay aging and extend lifespan in various model organisms. However, the long‐term effects of MR diet on the gut microbiome composition remain unclear. To study this, male mice were started on MR and control diet regimens at 6 months and continued until 22 months of age. MR mice have reduced body weight, fat mass percentage, and bone mineral density while having increased lean mass percentage. MR mice also have increased insulin sensitivity along with increasing indirect calorimetry markers such as energy expenditure, oxygen consumption, carbon dioxide production, and glucose oxidation. Fecal samples were collected at 1 week, 18 weeks, and 57 weeks after the diet onset for 16S rRNA amplicon sequencing to study the gut microbiome composition. Alpha and beta diversity metrics detected changes occurring due to the timepoint variable, but no changes were detected due to the diet variable. The results from LEfSe analysis surprisingly showed that more bacterial taxa changes were linked to age rather than diet. Interestingly, we found that the long‐term MR diet feeding induced smaller changes compared to short‐term feeding. Specific taxa changes due to the diet were observed at the 1 or 18‐week time points, including Ileibacterium, Odoribacter, Lachnoclostridium, Marinifilaceae, and Lactobacillaceae. Furthermore, there were consistent aging‐associated changes across both groups, with an increase in Ileibacterium and Erysipelotrichaceae with age, while Eubacterium_coprostanoligenes_group, Ruminococcaceae, Peptococcaceae, and Peptococcus decreased with age.

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Sexual dimorphism in the peripheral metabolic homeostasis and behavior in the TgF344‐AD rat model of Alzheimer's disease

Cited by 13 publications

References 51 publications

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats

Long term methionine restriction: Influence on gut microbiome and metabolic characteristics

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