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

Kelberman, Michael A.; Rorabaugh, Jacki M.; Anderson, Claire R.; Marriott, Alexia; DePuy, Seth D.; Rasmussen, Kurt; McCann, Katharine E.; Weiss, Jay M.

doi:10.1016/j.neurobiolaging.2023.01.016

Cited by 19 publications

(15 citation statements)

References 95 publications

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“…In clinical AD and animal models of the disease, loss of NE in terminal regions is often accompanied by increased LC firing rates, β-adrenergic receptor sensitivity, and NE turnover, which likely represent compensatory mechanisms that are engaged to maintain normal noradrenergic tone (Goodman et al, 2021;Iannitelli et al, 2023;Kelberman et al, 2022Kelberman et al, , 2023Rorabaugh et al, 2017;Weinshenker, 2018). Although the NE measures in the present experiment were obtained in 13-month-old rats, we recently showed that these compensatory mechanisms begin much earlier, with hyperactive evoked responses in LC neurons of 6-month-old AD rats (Kelberman et al, 2023). Consumption of a high-fat diet has been linked previously with loss of LC neurons in aged rats (Chou et al, 2022), and the present findings also show that long-term consumption of the Western diet significantly blunted the compensatory increase in NE turnover.…”

Section: Discussionmentioning

confidence: 99%

“…As we have previously reported, AD rats at a later stage have lower hippocampal NE levels than WT rats (Goodman et al, 2021; Kelberman et al, 2022; Rorabaugh et al, 2017). In clinical AD and animal models of the disease, loss of NE in terminal regions is often accompanied by increased LC firing rates, β‐adrenergic receptor sensitivity, and NE turnover, which likely represent compensatory mechanisms that are engaged to maintain normal noradrenergic tone (Goodman et al, 2021; Iannitelli et al, 2023; Kelberman et al, 2022, 2023; Rorabaugh et al, 2017; Weinshenker, 2018). Although the NE measures in the present experiment were obtained in 13‐month‐old rats, we recently showed that these compensatory mechanisms begin much earlier, with hyperactive evoked responses in LC neurons of 6‐month‐old AD rats (Kelberman 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: Discussionmentioning

confidence: 99%

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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“…At 16 months of age, these rats also exhibited impaired spatial reversal learning, but notably designer receptors exclusively activated by designer drugs (DREADD)-stimulation of the LC rescued learning in these animals 32 . Specific activation patterns of the LC were associated with the maintenance of memory performance, as well as LC fiber density 33 , suggesting that targeting the signaling capabilities of the LC in the earliest stages of the disease may be critical. Our results align with this and demonstrate the urgency of maintaining LC health and halting the spreading of tau to the MTL to delay cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Bueichekú,

Diez,

Kim

et al. 2024

Nat Aging

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Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer’s disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC’s selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC–medial temporal lobe–limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC’s selective vulnerability to Alzheimer’s disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

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“…The LEC is the first cortical region to undergo end-stage cellular neurodegeneration 5 in AD, specifically, Layer II 2 excitatory cells 7 . Conversely, one of the earliest pathophysiological alterations seen in both humans with AD, and in mouse models of early- and late-onset AD pathology 3,4,11 is altered local circuit excitability 6,61,62 . In agreement with our ex vivo mechanistic cellular findings here, hyperactivity has been shown to preferentially emerge in the LEC region in vivo 6 .…”

Section: Discussionmentioning

confidence: 99%

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Goettemoeller,

Banks,

Kumar

et al. 2023

Preprint

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Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability1. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer’s Disease2-4. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type-specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer’s. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. Furthermore, the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression, likely resulting from PV-interneuron variability between the two regions based on physiological and proteomic evaluations. Interestingly, entorhinal hAPP-induced hyperexcitability was quelled by co-expression of human Tau at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

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

Cited by 19 publications

References 95 publications

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

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

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

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