Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease

Neurobiology of Aging, Год журнала: 2023, Номер 125, С. 98 - 108

Опубликована: Фев. 1, 2023

Язык: Английский

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Protective effects of polydatin amphiphilic chitosan nanocarriers against an aluminum chloride-induced model of Alzheimer’s disease in rats: relevance to its anti-inflammatory and antioxidant effects

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

Язык: Английский

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Causal relationship between dietary habits and Alzheimer's disease risk: a univariable and multivariable Mendelian randomization study

Food & Function, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The objective of this study was to evaluate the causal link between dietary habits and Alzheimer's disease (AD), utilizing a two-sample Mendelian randomization approach.

Язык: Английский

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

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Март 22, 2023

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

Язык: Английский

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The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

eNeuro, Год журнала: 2022, Номер 10(1), С. ENEURO.0483 - 22.2022

Опубликована: Дек. 9, 2022

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) Parkinson's (PD), respectively. onset these pathologies coincides with loss fibers LC target regions emergence prodromal symptoms including sleep disturbances anxiety. Paradoxically, are indicative a hyperactivity phenotype, rather than predicted norepinephrine (NE) transmission following damage, suggesting engagement complex compensatory mechanisms. Because current therapeutic efforts targeting early disease, interest has grown, it critical to identify links between dysfunction. We employed LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages axons, model changes LC-NE system pertinent AD PD male female mice. DSP-4 (two doses 50 mg/kg, one week apart) induced axon degeneration, triggered neuroinflammation oxidative stress, reduced tissue NE levels. There was no cell death or firing, but transcriptomics revealed expression genes that define identity other relevant neurodegenerative disease. Despite dramatic fibers, turnover signaling were elevated terminal associated anxiogenic phenotypes multiple behavioral tests. These results represent comprehensive analysis how responds axon/terminal damage reminiscent at molecular, cellular, systems, levels, provides potential mechanisms underlying neuropsychiatric symptoms.

Язык: Английский

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

Journal of Neurochemistry, Год журнала: 2023, Номер 168(5), С. 801 - 821

Опубликована: Июнь 30, 2023

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

Язык: Английский

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Quantification and correlation of amyloid-β plaque load, glial activation, GABAergic interneuron numbers, and cognitive decline in the young TgF344-AD rat model of Alzheimer’s disease

Frontiers in Aging Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Фев. 12, 2025

Background Animal models of Alzheimer’s disease (AD) are essential tools for investigating pathophysiology and conducting preclinical drug testing. In this study, we examined neuronal glial alterations in the hippocampus medial prefrontal cortex (mPFC) young TgF344-AD rats correlated these changes with cognitive decline amyloid-β plaque load. Methods We compared non-transgenic littermate aged 7–8 months age. systematically quantified β-amyloid plaques, astrocytes, microglia, four different subtypes GABAergic interneurons (calretinin-, cholecystokinin-, parvalbumin-, somatostatin-positive neurons), newly generated neurons hippocampus. Spatial learning memory were assessed using Barnes maze test. Results Young had a large number amyloid plaques both mPFC, together pronounced increase microglial cell numbers. Astrocytic activation was significant mPFC. Cholecystokinin-positive numbers decreased transgenic rats, but calretinin-, not altered. Adult neurogenesis affected by genotype. spatial impairments, deficit did correlate or cellular brain. hippocampus, negatively cholecystokinin-positive neuron astrocytes. Conclusion Pronounced neuropathological found mPFC including loss hippocampal interneurons. Some load, impairment.

Язык: Английский

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Early emergence of motivational and hedonic feeding deficits in the TgF344-AD rat model of Alzheimer’s disease

Frontiers in Aging Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Апрель 28, 2025

Introduction Alzheimer’s disease (AD) is characterized by progressive cognitive decline and has a long prodromal phase during which subclinical deficits neuropsychiatric symptoms may begin to emerge. Apathy, defined as lack of motivation or volition, increasingly recognized core feature potentially early marker AD. Despite its significance, apathy-like behavior been underexplored in transgenic models Methods We performed longitudinal analysis using the well-established TgF344-AD rat model. compared male female wildtype rats on hedonic (palatable food intake) motivational (progressive ratio) assays (3—4 months), intermediate (6–7 later (9–10 months) stages adulthood. Results found that exhibited persistent feeding, emerging at 3–4 months 6–7 months, respectively. During battery tests conducted after 12–14 age, were impaired spatial working memory but also showed wide-ranging exploratory behavior, be indicative an loss investigatory drive. Conclusion Our findings highlight valuable model for studying AD underscore need consider sex differences research better understand this disease.

Язык: Английский

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Probiotic supplement as a promising strategy in early tau pathology prevention: Focusing on GSK-3β?

Frontiers in Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Март 22, 2023

Neurofibrillary tangles (NFT) is one of the hallmarks Alzheimer’s disease (AD). Recent research suggests that pretangle tau, soluble precursor NFT, an initiator for AD pathogenesis, thus targeting tau pathology may be a promising early intervention focus. The bidirectional communications between gut and brain play crucial role in health. compromised gut-brain axis involved various neurodegenerative diseases including AD. However, most on relationship microbiome have focused amyloid-β. In this mini review, we propose to target preclinical stages with microbiota interventions such as probiotic supplementation. We discuss importance starts decades before onset clinical symptoms, potential focusing regulation hyperphosphorylation. A particular focus GSK-3β, protein kinase at interface phosphorylation, diabetes mellitus.

Язык: Английский

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Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2024, Номер 16(1)

Опубликована: Май 31, 2024

Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline dementia. Recent neuroimaging and pharmacological studies left frontoparietal network functional connectivity (LFPN-FC) confers resilience beta-amyloid (Aβ)-related preclinical sporadic autosomal dominant Alzheimer's disease (AD), as well LC-related changes. Given LFPN LC play important roles attention, attention deficits have been observed early process, we examined whether LFPN-FC structural health attenuate attentional context of AD pathology. 142 participants from Harvard Aging Brain Study who underwent resting-state MRI, imaging, PiB(Aβ)-PET, up to 5 years follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated integrity (measured average five continuous voxels with highest intensities images) or Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal mixed effect analyses associations between DSST (i) two-way interactions baseline (or LFPN-FC) PiB (ii) three-way interaction integrity, LFPN-FC, PiB. Baseline age, sex, education covariates. At baseline, lower but not was related worse performance. Longitudinally, a faster decline, especially > 10.38 CL. Lower steeper on independent elevated levels (> 46 CL), higher an attenuated DSST, despite presence integrity. Our findings demonstrate can provide Aβ-related decline. However, when Aβ accumulates LC's resources may be depleted, functioning cortical target regions LC, such additional sustain AD. These results critical insights into correlates contributing individual variability risk versus

Язык: Английский

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