Canine Cognitive Dysfunction and Alzheimer’s Disease – Two Facets of the Same Disease?

Mihevc, Sonja Prpar; Majdič, Gregor

doi:10.3389/fnins.2019.00604

Cited by 68 publications

(51 citation statements)

References 201 publications

(281 reference statements)

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“…Some literature exists on the impact of gonadectomy on cognitive function in dogs, most notably regarding Canine Cognitive Dysfunction (CCD), which is a behavioral syndrome affecting older dogs that shares many pathophysiological and behavioral hallmarks with human Alzheimer's Disease (AD), including progressive cognitive impairment, loss of normal sleep patterns, increased anxiety, and aimless wandering as well as Amyloid-beta and possibly tau pathology in the brain [230][231][232]. In this context, female and gonadectomized dogs have been shown to be significantly more likely to show signs of CCD than intact and male dogs in a study of n = 325 geriatric dogs aged nine or older [233].…”

Section: Cognitive Functionmentioning

confidence: 99%

Desexing Dogs: A Review of the Current Literature

Urfer

Kaeberlein

2019

Animals

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Background: Desexing dogs is promoted for population control, preventative healthcare, and behavior modification. Common methods are orchiectomy and ovariectomy/ovariohysterectomy. GnRH superagonist implants are available in some areas. Alternative methods like vasectomy and salpingectomy/hysterectomy are uncommon. The terminology used to describe desexing is inconsistent and contradictory, showing a need for the adaption of standardized terminology. Population Control: Surprisingly, empirical studies show no effects of desexing on population control in companion and shelter dogs despite desexing being consistently recommended in the literature. There is evidence for a population control effect in free-roaming dogs, where desexing also has benefits on zoonotic disease and bite risk. Population control in free-roaming dogs is mostly correlated with female, not male desexing. Health and Lifespan: Desexing affects numerous disease risks, but studies commonly neglect age at diagnosis and overall lifespan, age being by far the most important risk factor for most diseases. We argue that lifespan is a more important outcome than ultimate cause of death. A beneficial effect of desexing on lifespan is consistently demonstrated in females, while evidence for a beneficial effect in males is inconsistent. Studies are likely biased in desexing being a proxy for better care and desexed dogs having already lived to the age of desexing. Desexing reduces or eliminates common life-limiting diseases of the female reproductive system such as pyometra and mammary tumors, while no analogous effect exists in males. Disease risks increases across sexes and breeds include cruciate ligament rupture, various cancers, and obesity. Urinary incontinence risk is increased in females only. Various other disease risk changes show considerable variability between breeds and sexes. Behavioral Effects: Desexed males show reduced libido, roaming, conspecific mounting, and urinary marking frequency, as well as reduced male dog-directed aggression in a majority of males desexed for behavioral reasons. There is a detrimental effect on the risk and progression of age-related cognitive dysfunction. Desexed dogs may be less likely to cause bite injuries across sexes. The evidence for other effects such as human-directed aggression, human or object mounting, resource guarding, or shyness and anxiety is inconsistent and contradictory. There are few studies specific to females or individual breeds. Conclusions: The evidence for a beneficial effect of desexing is stronger in female than in male dogs; however, there is significant variation between breeds and sexes, and more research is needed to further elucidate these differences and to arrive at individualized evidence-based recommendations for clinical practice.

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Section: Cognitive Functionmentioning

confidence: 99%

Desexing Dogs: A Review of the Current Literature

Urfer

Kaeberlein

2019

Animals

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“…As noted above, we and others have found that oral infection of mice with P. gingivalis results in translocation to the brain, resulting in neurodegeneration and AD pathology, while other oral bacteria did not translocate . Because dogs are naturally infected with the closely related species, P. gulae, and commonly develop both periodontal disease and canine cognitive dysfunction associated with cerebral neuropathology, including amyloidosis, tau hyperphosphorylation and neuronal loss that resembles AD in humans, we aimed to examine the presence of P. gulae and associated gingipain proteases in dogs and investigate the pharmacology of the selective Kgp inhibitor COR388 in these animals. The prevalence of periodontal disease in dogs increases with age, with 40.8% of dogs 1‐4 years old, and 53.6% of dogs 5‐8 years old, having evidence of the disease, with prevalence increasing to >85% in dogs older than 8 years of age .…”

Section: Introductionmentioning

confidence: 99%

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Arastu‐Kapur¹,

Mai²,

Raha³

et al. 2020

Pharmacology Res & Perspec

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COR388, a small‐molecule lysine‐gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine‐gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28‐day dose‐response study, COR388 inhibited the lysine‐gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine‐gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine‐gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine‐gingipain and eliminating P. gingivalis infection in humans.

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“…As dogs and humans share their environment and have similar lifestyles, they also suffer from some similar diseases. For instance, canine cognitive dysfunction is in many aspects similar to human Alzheimer’s disease [ 29 ] and represent an interesting model to study this debilitating disease. Canine cognitive dysfunction is interesting disease for cell replacement therapy by transplanting neurally differentiated ASCs into the canine brain.…”

Section: Discussionmentioning

confidence: 99%

Neural differentiation of canine mesenchymal stem cells/multipotent mesenchymal stromal cells

et al. 2020

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Background: The ability of adipose tissue-derived multipotent mesenchymal stromal cells/mesenchymal stem cells (ASCs) to differentiate in neural lineages promises progress in the field of regenerative medicine, especially for replacing neuronal tissue damaged by different neurological disorders. Reprogramming of ASCs can be induced by the growth medium with neurogenic inductors and specific growth factors. We investigated the neural differentiation potential of canine ASCs using several growth media (KEM, NIMa, NIMb, NIMc) containing various combinations of neurogenic inductors: B27 supplement, valproic acid, forskolin, N2-supplement, and retinoic acid. Cells were first preconditioned in the pre-differentiation neural induction medium (mitogenically stimulated; STIM1), followed by the induction of neuronal differentiation. Results: After 3, 6, and 9 days of neural induction, elongated neural-like cells with bipolar elongations were observed, and some oval cells with light nuclei appeared. The expression of neuronal markers tubulin beta III (TUBB3), neurofilament H (NF-H), microtubule-associated protein-2 (MAP2), and glial fibrillary acidic protein (GFAP) was observed using immunocytochemistry, which confirmed the differentiation into neurons and glial cells. Flow cytometry analysis showed high GFAP expression (between 70 and 90% of all cells) after cells had been growing three days in the neural induction medium a (NIMa). Around 25% of all cells also expressed adult neuronal markers NF-H and MAP2. After nine days of ASCs differentiation, the expression of all neural markers was reduced. There were no differences between the neural differentiation of ASCs isolated from female or male dogs. Conclusions: The differentiation repertoire of canine ASCs extends beyond mesodermal lineages. Using a defined neural induction medium, the canine ASCs differentiated into neural lineages and expressed markers of neuronal and glial cells, and also displayed the typical neuronal morphology. Differentiated ASCs can thus be a source of neural cellular lineages for the regenerative therapy of nerve damage and could be useful in the future for therapy or the modelling of neurodegenerative diseases.

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Canine Cognitive Dysfunction and Alzheimer’s Disease – Two Facets of the Same Disease?

Cited by 68 publications

References 201 publications

Desexing Dogs: A Review of the Current Literature

Desexing Dogs: A Review of the Current Literature

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Neural differentiation of canine mesenchymal stem cells/multipotent mesenchymal stromal cells

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