Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

Bernaud, Victoria E.; Bulen, Haidyn L.; Peña, Verónica; Koebele, Stephanie V.; Northup-Smith, Steven N.; Manzo, Alma A; Sanchez, Maria Valenzuela; Opachich, Zorana; Ruhland, Ashley M; Bimonte‐Nelson, Heather A.

doi:10.1038/s41598-022-18415-1

Cited by 18 publications

(21 citation statements)

References 73 publications

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“…Impaired spatial memory in the Barnes maze has been observed in TgF344-AD rats starting from 4 months of age, suggesting hippocampal impairments are already present during the pre-plaque stage of AD as is observed in this study ( Fowler et al, 2022 ). In addition, working memory impairments and delayed memory retention have been observed in 6-month-old female TgF344-AD rats ( Bernaud et al, 2022 ). Moreover, cholinergic dysfunction and neuroinflammatory responses have been observed from 6 months onward in TgF344-AD rats ( Chaney et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Alterations in theta-gamma coupling and sharp wave-ripple, signs of prodromal hippocampal network impairment in the TgF344-AD rat model

Berg

Toen

Verhoye

et al. 2023

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (Aβ) and tau, which eventually leads to dementia. Disease-modifying therapies are still lacking, due to incomplete insights into the neuropathological mechanisms of AD. Synaptic dysfunction is known to occur before cognitive symptoms become apparent and recent studies have demonstrated that imbalanced synaptic signaling drives the progression of AD, suggesting that early synaptic dysfunction could be an interesting therapeutic target. Synaptic dysfunction results in altered oscillatory activity, which can be detected with electroencephalography and electrophysiological recordings. However, the majority of these studies have been performed at advanced stages of AD, when extensive damage and cognitive symptoms are already present. The current study aimed to investigate if the hippocampal oscillatory activity is altered at pre-plaque stages of AD. The rats received stereotactic surgery to implant a laminar electrode in the CA1 layer of the right hippocampus. Electrophysiological recordings during two consecutive days in an open field were performed in 4–5-month-old TgF344-AD rats when increased concentrations of soluble Aβ species were observed in the brain, in the absence of Aβ-plaques. We observed a decreased power of high theta oscillations in TgF344-AD rats compared to wild-type littermates. Sharp wave-ripple (SWR) analysis revealed an increased SWR power and a decreased duration of SWR during quiet wake in TgF344-AD rats. The alterations in properties of SWR and the increased power of fast oscillations are suggestive of neuronal hyperexcitability, as has been demonstrated to occur during presymptomatic stages of AD. In addition, decreased strength of theta-gamma coupling, an important neuronal correlate of memory encoding, was observed in the TgF344-AD rats. Theta-gamma phase amplitude coupling has been associated with memory encoding and the execution of cognitive functions. Studies have demonstrated that mild cognitive impairment patients display decreased coupling strength, similar to what is described here. The current study demonstrates altered hippocampal network activity occurring at pre-plaque stages of AD and provides insights into prodromal network dysfunction in AD. The alterations observed could aid in the detection of AD during presymptomatic stages.

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Section: Discussionmentioning

confidence: 99%

Alterations in theta-gamma coupling and sharp wave-ripple, signs of prodromal hippocampal network impairment in the TgF344-AD rat model

Berg

Toen

Verhoye

et al. 2023

Front. Aging Neurosci.

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“…Estrous cycle was not monitored in the present study. It is not likely that genotype-induced changes in estrous cycle contributed to sex differences, however, because estrous is age-typical in 6-, 9-, and 12-month-old female TgF344-AD rats (Bernaud et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Estrous cycle was not monitored in the present study. It is not likely that genotype‐induced changes in estrous cycle contributed to sex differences, however, because estrous is age‐typical in 6‐, 9‐, and 12‐month‐old female TgF344‐AD rats (Bernaud et al, 2022). Nonetheless, it remains possible that the dietary manipulation disrupted the estrous cycle and/or that most of the rats were in the same estrous phase.…”

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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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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“…One study showed a difference between TgF344-AD and WT rats at 10-11 months using the Morris water maze (MWM). 48 Others found a similar pattern at 12 months of age using the radial-arm maze, 49 and at 15 months of age using the Barnes maze test. 50 These studies together with ours, which show that TgF344-AD rats exhibit cognitive deficits at 11-but not 9-months of age, strongly support that the TgF344-AD rat model incorporates aging as a risk factor for Alzheimer's.…”

Section: Tgf344-ad Ratsmentioning

confidence: 77%

Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer’s disease in females

Ndukwe,

Serrano,

Rockwell

et al. 2023

Preprint

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Nearly two-thirds of patients with Alzheimer′s are women. Identifying therapeutics specific for women is critical to lowering their elevated risk for developing this major cause of adult dementia. Moreover, targeting epigenetic processes that regulate multiple cellular pathways is advantageous given Alzheimer′s multifactorial nature. Histone acetylation is an epigenetic process heavily involved in memory consolidation. Its disruption is linked to Alzheimer′s. Through our computational studies, we predicted that the investigational drug RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) has repurposing potential for Alzheimer′s. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier. We investigated the RG2833 therapeutic potential in TgF344-AD rats, which are a model of Alzheimer′s that exhibits age-dependent progression, thus mimicking this aspect of Alzheimer′s patients that is difficult to establish in animal models. We investigated the RG2833 effects on cognitive performance, gene expression, and AD-like pathology in 11-month TgF344-AD female and male rats. A total of 89 rats were used: wild type n = 45 (17 females, 28 males), and TgF344-AD n = 44 (24 females, 20 males)] across multiple cohorts. No obvious toxicity was detected in the TgF344-AD rats up to 6 months of RG2833-treatment starting at 5 months of age administering the drug in rodent chow at ≈30mg/kg of body weight. We started treatment early in the course of pathology when therapeutic intervention is predicted to be more effective than in later stages of the disease. The drug-treatment significantly mitigated hippocampal-dependent spatial memory deficits in 11-month TgF344-AD females but not in males, compared to wild type littermates. This female sex-specific drug effect has not been previously reported. RG2833-treatment failed to ameliorate amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. However, RNAseq analysis of hippocampal tissue from TgF344-AD rats showed that drug-treatment in females upregulated the expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at P < 0.05, false discovery rate < 0.05, and fold-change ≥ 1.5. Our data suggest that histone modifying therapeutics such as RG2833 improve cognitive behavior by modulating the expression of immediate early, neuroprotective and synaptic plasticity genes. Our preclinical study supports that RG2833 has therapeutic potential specifically for female Alzheimer′s patients. RG2833 evaluations using other AD-related models is necessary to confirm our findings.

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Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

Cited by 18 publications

References 73 publications

Alterations in theta-gamma coupling and sharp wave-ripple, signs of prodromal hippocampal network impairment in the TgF344-AD rat model

Alterations in theta-gamma coupling and sharp wave-ripple, signs of prodromal hippocampal network impairment in the TgF344-AD rat model

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

Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer’s disease in females

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