The Role of Aging and the Immune System in Canine Degenerative Myelopathy
Canine degenerative myelopathy (DM) is a non-painful, slowly progressive nervous system disease that affects adult dogs later in life. Clinical signs include loss of coordination and progressive weakness of the hind limbs with eventual paralysis and spread to the fore limbs and brain stem. Diagnosis and treatment of DM are challenging because the early clinical signs resemble those of other acquired spinal cord diseases and affected dogs may have concurrent neurologic and orthopedic problems, such as osteoarthritis, that are common with advancing age. Canine DM also has similarities with some forms of amyotrophic lateral sclerosis (ALS) in people. The AKC Canine Health Foundation (CHF) and our donors have provided funding for DM research for over two decades so that veterinary and comparative medical researchers can continue to improve our understanding of this complex disease.
Dr. Christine Sibigtroth (now Dr. Toedebusch) received an AKC Canine Health Foundation Clinician-Scientist Fellowship in 2015 to study the role of the immune system in DM progression. Under the mentorship of CHF-funded researchers Dr. Joan Coates and Dr. Michael Garcia at the University of Missouri, her work focused on microglia – the primary immune cell of the central nervous system (CNS). Microglia can promote inflammation to clear invading infection or maintain health by clearing debris and dead neurons. Think of them as the surveillance and first responders of the CNS that activate to fight pathogens (pro-inflammatory) or repair and clean-up after insult (anti-inflammatory) depending on the body’s needs.
Through incompletely understood mechanisms, microglia play a central role in age-related neurodegenerative disease in several species (mice, dogs, and humans). Aged microglia may have a diminished ability to move throughout the CNS and they have a greater tendency to be in a pro-inflammatory state. During her fellowship, Dr. Toedebusch compared microglia in the lumbar spinal cord of neurologically normal aging dogs and dogs with DM. DM-affected dogs had more microglia in the lumbar spine compared to aged normal dogs. However, both groups showed a similar microglial pro-inflammatory profile.1
Given this unexpected finding, coupled with age as a major risk factor for DM, Dr. Toedebusch hypothesized that aging dog spinal cord microglia are pro-inflammatory, which may contribute to the onset of DM. To test this hypothesis, she and her research team recently re-examined their data in the context of age – comparing the microglial response between neurologically normal young and aging dogs. Results, recently published in GeroScience,2 showed regional differences in microglial activation and inflammatory gene expression throughout the spinal cord. Specifically, aging dogs had more microglia in the lumbar spinal cord with an increased proportion of activated cells. Also, the lumbar spinal cord in aging dogs had increased pro- and anti-inflammatory gene expression, while gene expression in the cervical spinal cord was similar between groups. These data suggest that microglia in the lumbar spinal cord of aging dogs are primed for activation. Researchers concluded that microglial priming, advancing age, and a mutation in the gene that codes for superoxide dismutase 1 (SOD1) are all risk factors for development of clinical signs of canine DM.
These results are another important step in understanding, diagnosing, treating, and eventually preventing canine DM and potentially ALS in humans. CHF educational grants and canine health research funding have supported several key discoveries in this process - including the discovery of the SOD1 mutation, a cerebrospinal fluid biomarker that can be useful for pre-mortem diagnosis in dogs, and the immune system changes described here. Learn more about these programs and discoveries through the following resources:
- AKC Canine Health Foundation Clinician-Scientist Fellowship Program
- Canine Health Bytes webinar “Canine Degenerative Myelopathy: From Gene Mutation Discovery to Clinical Trials” and summary article.
- “Unraveling Canine Degenerative Myelopathy” and researcher spotlight on Dr. Joan Coates in Discoveries – Summer 2018.
- Current CHF health research grants for canine degenerative myelopathy.
Thanks to CHF’s dedicated supporters and funded researchers, we are making great strides in the fight against canine degenerative myelopathy. To support this effort, please donate at www.akcchf.org/donateRPA.
1. Toedebusch CM, Snyder JC, Jones MR, Garcia VB, Johnson GC, Villalón EL, Coates JR, Garcia ML (2018). Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis. Mol Cell Neurosci 88:148–157.
2. Toedebusch, C.M., Garcia, V.B., Snyder, J.C. et al. GeroScience (2019). Lumbar spinal cord microglia exhibited increased activation in aging dogs compared with young adult dogs.
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