Canine Cognitive Dysfunction and Alzheimer's Disease - Two Facets of the Same Disease?

Abstract

Neurodegenerative diseases present a major and increasing burden in the societies worldwide. With aging populations, the prevalence of neurodegenerative diseases is increasing, yet there are no effective cures and very few treatment options are available. Alzheimer's disease is one of the most prevalent neurodegenerative conditions and although the pathology is well studied, the pathogenesis of this debilitating illness is still poorly understood. This is, among other reasons, also due to the lack of good animal models as laboratory rodents do not develop spontaneous neurodegenerative diseases and human Alzheimer's disease is only partially mimicked by transgenic rodent models. On the other hand, older dogs commonly develop canine cognitive dysfunction, a disease that is similar to Alzheimer's disease in many aspects. Dogs show cognitive deficits that could be paralleled to human symptoms such as disorientation, memory loss, changes in behavior, and in their brains, beta amyloid plaques are commonly detected both in extracellular space as senile plaques and around the blood vessels. Dogs could be therefore potentially a very good model for studying pathological process and novel treatment options for Alzheimer's disease. In the present article, we will review the current knowledge about the pathogenesis of canine cognitive dysfunction, its similarities and dissimilarities with Alzheimer's disease, and developments of novel treatments for these two diseases with a focus on canine cognitive dysfunction.

Keywords: Alzheimer’s disease; TAU; amyloid beta; animal model; brain; canine cognitive dysfunction; neurodegeneration; treatment.

FIGURE 1

Protein sequences alignments between dog and human amyloid-beta precursor protein (APP) and TAU. (A) The alignment of the longest canine APP isoform (APP-770) sequence with protein sequence of human APP. Aligned sequences share 96.9% amino acid identity and 98.3% similarity. Of note, the sequence identity of canine APP-695 isoform, the predominant APP isoform in the canine brain, and human APP is 87.5%. Highlighted is Aβ domain and underlined the membrane bound part of this domain. (B) Domain structure of APP. Isoform APP-770 is depicted. HBD1/GFLD, heparin binding domain 1/growth factor like domain; CuBD, copper binding domain; ZnBD, zinc binding domain; KPI, Kunitz-type protease inhibitor domain (not present in APP-695); Aβ, amyloid beta domain, the latter anchors APP in the cell membrane. The α-, β-, and γ-secretase cleavage sites are directly adjacent or inside the Aβ domain region, which is also most mutation prone, thus enabling alternative cleavage of APP and its divergent aggregation propensities. (C) Alignment of the longest TAU protein isoform, out of six existing, of dog and human TAU. Aligned TAU sequences share 81.6% amino acid identity and 84.4% similarity. Highlighted are four microtubule-binding regions (4R). (D) Domain structure of TAU. The basic organization is shown. NTR, N-terminal region; PRR, proline-rich region; 4R, four microtubule-binding regions (some isoforms have three); CTR, C-terminal region. The PRR and 4R domains are subject of most posttranslational modifications, while the CTR enables interactions with microtubules and plasma membrane. EMBOSS Needle pairwise sequence alignment (Madeira et al., 2019) was performed. A line (|) indicates positions which have a single, fully conserved residue. A colon (:) indicates conservation between groups of strongly similar properties and a dot (.) indicates conservation between groups of weakly similar properties. The domain organization was depicted by software illustrator of biological sequences (IBS) (Liu et al., 2015). Figure made by the authors.

FIGURE 2

Presence of Aβ in the cerebral cortex of a dog with CCD. The dense plaques detected in superficial cortical layers and diffuse plaques in deeper layers of prefrontal cortex. The dog was 17-years-old of a mixed breed. Immunoperoxidase staining with antibodies against Aβ (purified anti-β-Amyloid, 17-24 Antibody, BioLegend, #800701) with diaminobenzidine (DAB) as chromogen (brown), counter stained with hematoxylin. Original microphotograph made by the authors.

FIGURE 3

Amyloid beta (red) detected by immunofluorescence staining in the wall of a leptomeningeal blood vessel in the frontal cortex from a 15-years-old Pit Bull Terrier. Nuclei were counterstained with DAPI (blue). The antibody employed is the same as in Figure 2. Original microphotograph made by the authors.