Canine Cognitive Dysfunction (CCD) scores correlate with amyloid beta 42 levels in dog brain tissue

Urfer, Silvan R.; Darvas, Martin; Czeibert, Kálmán; Sándor, Sára; Promislow, Daniel; Creevy, Kate E.; Kubinyi, Enikő; Kaeberlein, Matt

doi:10.1007/s11357-021-00422-1

Cited by 27 publications

(18 citation statements)

References 40 publications

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“…Alzheimer’s disease has been causing a substantial health burden, and its prevalence is increasing with global population ageing ( Urfer et al, 2021 ). After decades of research, scientists have concluded that Aβ extracellular plaques are directly linked to the neuropathological events such as synaptic and neuronal cell death ( Cisternas et al, 2020 ; Fracassi et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

The Food Additive β-Caryophyllene Exerts Its Neuroprotective Effects Through the JAK2-STAT3-BACE1 Pathway

Zhang

Huang

Wang

et al. 2022

Front. Aging Neurosci.

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Despite extensive research on Alzheimer’s disease (AD), its diagnosis and treatment remain challenging, and no effective therapies are currently available. Amyloid β (Aβ) extracellular plaques and intracellular neurofibrillary tangles are the histological characteristics of AD that have been directly linked to neuropathological events such as synaptic and neuronal cell loss. In this study, we explored whether the “JAK2-STAT3-BACE1” pathway is involved in neuroprotection conferred by the food flavouring agent β-caryophyllene (BCP). PC-12 cells with overexpressed amyloid-β protein precursor (APP) were utilised to construct an AD model in vitro, which was then split into four groups, namely control, empty vector, APP overexpression, and BCP (5, 10, and 20 μM). CCK-8 was used to evaluate cell viability, immunofluorescence was utilised to examine synaptic morphology, and quantitative real-time polymerase chain reaction and western blot were used to examine gene and protein expression levels. The relative expression levels of JAK2, STAT3, and BACE1 mRNA in the transfected PC-12 cells were found to be significantly upregulated. The cell morphology altered dramatically 72 h after transfection, becoming rounder, with a decrease in cell number. BCP exhibited the potential to dramatically increase PC-12 cell viability while protecting cell morphology. BCP inhibited APP, JAK2, STAT3, BACE1 mRNA and BACE1 protein overexpression, as well as JAK2 and STAT3 hyperphosphorylation. Molecular docking simulated the docking of BCP with JAK2, STAT3, BACE1, CB2. And JAK2 was found to be the most stable protein. In conclusion, inhibition of the “JAK2-STAT3-BACE1” signalling pathway may be one of the mechanisms through which BCP protects neurons and antagonises Aβ’s neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

The Food Additive β-Caryophyllene Exerts Its Neuroprotective Effects Through the JAK2-STAT3-BACE1 Pathway

Zhang

Huang

Wang

et al. 2022

Front. Aging Neurosci.

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“…Several studies have suggested dogs as promising models for aging [1][2][3][4] because dogs have a much shorter lifespan than humans, yet undergo a highly similar aging course and are prone to develop analogous age-related pathologies. Importantly, a proportion of old dogs develop canine cognitive dysfunction (CCD), which shares many similarities with human Alzheimer's disease (AD), in both symptoms and brain pathology [5][6][7]. Dogs, therefore, may gain a key role in dementia research, as this form of agerelated neurodegeneration does not naturally occur in most laboratory model organisms, including rodents.…”

Section: Introductionmentioning

confidence: 99%

Poly(A) RNA sequencing reveals age-related differences in the prefrontal cortex of dogs

et al. 2022

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Dogs may possess a unique translational potential to investigate neural aging and dementia because they are prone to age-related cognitive decline, including an Alzheimer’s disease–like pathological condition. Yet very little is known about the molecular mechanisms underlying canine cognitive decline. The goal of the current study was to explore the transcriptomic differences between young and old dogs’ frontal cortex, which is a brain region often affected by various forms of age-related dementia in humans. RNA isolates from the frontal cortical brain area of 13 pet dogs, which represented 7 different breeds and crossbreds, were analyzed. The dogs were euthanized for medical reasons, and their bodies had been donated by their owners for scientific purposes. The poly(A) tail RNA subfraction of the total transcriptome was targeted in the sequencing analysis. Cluster analyses, differential gene expression analyses, and gene ontology analyses were carried out to assess which genes and genetic regulatory mechanisms were mostly affected by aging. Age was the most prominent factor in the clustering of the animals, indicating the presence of distinct gene expression patterns related to aging in a genetically variable population. A total of 3436 genes were found to be differentially expressed between the age groups, many of which were linked to neural function, immune system, and protein synthesis. These findings are in accordance with previous human brain aging RNA sequencing studies. Some genes were found to behave more similarly to humans than to rodents, further supporting the applicability of dogs in translational aging research.

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“…Dozens of studies have shown that signs of age-related neurodegeneration in dogs are often accompanied by cognitive dysfunction in learning and memory analogous to impairments often seen in aging and Alzheimer’s disease (Head, 2011, 2013; Milgram et al, 2004; Packer et al, 2018; Ruehl et al, 1995). Although the full complement of Alzheimer’s disease neuropathology has yet to be consistently observed in any naturally occurring non-human animal model, Alzheimer-like pathology, e.g., Aβ 1-42, increases with age in companion dogs (Urfer et al, 2021) and has been described in the context of diffuse plaque deposition that has been related to cognitive decrements in older dogs (Cotman and Head, 2008). There is also preliminary evidence for tauopathy, another feature of Alzheimer-like pathology, in the brains of dogs diagnosed with canine cognitive dysfunction (Abey et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project

Bray

Raichlen

Forsyth

et al. 2022

Preprint

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Canine Cognitive Dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer’s disease. Given that physical activity is believed to reduce risk of Alzheimer’s disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity—with several important covariates—as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = -0.10, 95% CI: -0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = -0.07, 95% CI: -0.09 to -0.05, p <0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p <0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer’s disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical-activity interventions.

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Canine Cognitive Dysfunction (CCD) scores correlate with amyloid beta 42 levels in dog brain tissue

Cited by 27 publications

References 40 publications

The Food Additive β-Caryophyllene Exerts Its Neuroprotective Effects Through the JAK2-STAT3-BACE1 Pathway

The Food Additive β-Caryophyllene Exerts Its Neuroprotective Effects Through the JAK2-STAT3-BACE1 Pathway

Poly(A) RNA sequencing reveals age-related differences in the prefrontal cortex of dogs

Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project

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