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. 2022 Jun;44(3):1269-1293.
doi: 10.1007/s11357-022-00533-3. Epub 2022 Mar 14.

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

Sára Sándor #  1 , Dávid Jónás #  2 , Kitti Tátrai  2   3 , Kálmán Czeibert  2 , Eniko Kubinyi  2
Affiliations

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

Sára Sándor et al. Geroscience. 2022 Jun.

Abstract

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.

Keywords: Aging; Dog; Prefrontal cortex; RNA sequencing.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The simplified analysis pipeline used for data analysis
Fig. 2
Fig. 2
Multidimensional scaling of the CPM (counts per million reads) values for each gene expressed in the samples. Distances between the individuals represent the pairwise differences in log-transformed fold changes. Coloring of the groups is according to the visibly distinguishable clusters. Abbreviations belonging to each animal have been included in Table 1
Fig. 3
Fig. 3
Venn diagram of all detected genes (a) and of the differentially expressed genes (b)
Fig. 4
Fig. 4
Two heatmaps showing the expression levels of the 3436 differentially expressed genes (DEGs) together with a cluster analysis of the individuals (shown on top of each heatmap) based on the DEGs. Here, the CL1_eto1 animal was excluded from the differential gene expression analysis. a DEGs with small (< 50%) fold change differences (2200 genes). b DEGs with large fold change differences (1236 genes). Genes with > 50% differences in fold change were classified as highly differentially expressed genes
Fig. 5
Fig. 5
(a) IGV picture of the CDKN2A gene and (b) the distribution of the observed, corrected CPKM values shown in a boxplot. Black dots on the boxplot correspond to the individual expression levels measured in the 6 young and 7 old studied dogs
Fig. 6
Fig. 6
Results of the gene ontology analysis. Gene ontology terms are ordered by fold enrichment and grouped by gene ontology classes (biological process: red; cellular components: blue; molecular function: green)
Fig. 7
Fig. 7
Results of the PSI analysis. a A scatter plot showing the estimated PSI indices in young vs. old animals. The PSI indices with > 20% difference are shown in red, while those with < 20% difference between the two cohorts are shown in gray. b A boxplot of PER3’s estimated PSI values with extremely divergent PSI indices between the young and old cohorts
Fig. 8
Fig. 8
Comparison of the differentially expressed genes in dogs with those published in mice [114] and in humans [40]. In the case of the mouse and human data, only those genes were considered that had homologs in dogs
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