Increased neurotoxic gliosis and blood-brain barrier dysregulation in canine cognitive dysfunction syndrome (CCD).

BACKGROUND: As Alzheimer's Disease (AD) and related dementias (ADRD) prevalence is projected to double by 2050, the urgency for relevant models to study its pathology intensifies. Aging is the primary risk factor for AD development and influenced by a myriad of factors including neurotoxic glial activation and BBB degradation; however, historically AD models consist of transgenic mouse in-vivo and in-vitro methods. While this offers many strengths, it is limited in their ability to mimic aging induced AD pathology. Currently, canine cognitive dysfunction (CCD) syndrome is being investigated as it is a natural and spontaneous disease with similar pathologies to AD and other dementias. Our lab and many others have worked extensively to characterize CCD pathology. However, the role of microglial and astrocytic activation and the interplay between the blood-brain barrier (BBB) have not been investigated. This study aims to fill this gap in knowledge in CCD and in turn its relation to human AD. We hypothesize that CCD-afflicted canines will exhibit increased neurotoxic glial activation and BBB degradation.

METHODS/RESULTS: We utilized immunohistochemistry (IHC), morphological analyses, and immunofluorescence to investigate CCD pathology comparing CCD negative and CCD positive dogs. In this study we see glial morphology consistent with those seen in neurotoxic glia in neurodegenerative disease, increased S100β/C3 astrocyte activation, decreased claudin-5 expression, and region-dependent perivascular AQP4 expression modulation in dogs with CCD, compared to those without CCD.

CONCLUSION: Our results further characterize glial and BBB roles in CCD pathogenesis and reinforces the strengths of modeling AD/ADRD in aging dogs.