Canine Cognitive Dysfunction Is Associated with Alzheimer’s Disease-Related Changes in the Brain Transcriptome and RNA Changes in Plasma Extracellular Vesicles

Abstract

Chronic, age-related diseases, such as Alzheimer’s disease (AD), can be diffcult to study longitudinally because humans have long lifespans and are highly heterogeneous. Recently, companion dogs have emerged as a promising model of AD because dogs: a) have a shorter lifespan than humans; b) are heterogeneous like humans; c) exposed to diverse human environments; and d) naturally develop canine cognitive dysfunction (CCD), similar to AD. However, the transcriptomic similarities between AD and CCD have not been evaluated, and emerging mechanisms of AD have not been explored in dogs. One such mechanism involves extracellular vesicles (EVs), ~100nm lipid bilayer particles that can package neurodegeneration-relevant cargo (e.g., RNAs, cytokines), export it to other cells, and contribute to aging/AD-relevant processes like inflammation. To better understand CCD and determine if EVs may play a role in it, we generated total transcriptome (RNA-seq) on cortex tissue and EVs isolated from plasma of young, old, and CCD dogs, and we evaluated cytokine expression in corresponding plasma samples via ELISAs. In the animals we studied, we observed functional differences between old healthy and CCD animals, reflected by Canine Dementia Scale scores (CADES; 6 and 57, respectively). In our RNA-seq analyses, we found marked age- and CCD-related transcriptome differences in the cortex (328 and 2673 differentially expressed genes, respectively), which mostly reflected changes in immune activation and neuronal health (similar to what has been observed in AD). Moreover, when we overlapped transcriptome data on the cortex and plasma EVs, we found a significant overlap in genes that were either up- or down-regulated in both samples (344 and 515, respectively). The processes related to these genes reflected changes in regulation of immune responses, as well as synaptic signaling. We also found evidence of CCL5 (RANTES, increased in AD) RNA in plasma EVs only in CCD samples, which corresponded with increased CCL5 expression in the brains of the same animals, although no differences were observed in plasma concentrations. While preliminary in nature, these results suggest that CCD is associated with AD-like transcriptomic changes in the brain, and with AD-relevant changes in EV cargo. Future studies are needed to determine the functional relevance of these data, but our results suggest the possibility of finding specific EV/RNA markers that could predict disease severity in CCD, and perhaps eventually in AD. NIA R01AG078859; CSU Catalyst for Innovative Partnership Award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.