TAU protein, another important factor in neurodegenerative diseases, is encoded by MAPT (microtubule associated protein tau) gene. Mutations in this gene have not been linked to AD, but cause a familial form of frontotemporal dementia (Olszewska et al., 2016). However, in human AD, intraneuronal NFTs composed of hyperphosphorylated TAU and misfolded insoluble TAU protein aggregates and extracellular Aβ inclusions are both present and necessary for the diagnosis of the disease. In AD NFTs form initially in the locus coeruleus, then entorhinal cortex and further progress to the hippocampus, anterior cingulate cortex, visual association area and finally to the primary visual cortex in the occipital lobe (Ossenkoppele et al., 2016; Hoenig et al., 2018). Interestingly, TAU neurofibrillary inclusions were only rarely identified in canine brain, for instance only in one dog in one study (Smolek et al., 2016) and in three dogs in another study (Schmidt et al., 2015). Increased phosphorylation of TAU was observed at some amino acid sites in canine brain, although no study so far confirmed the presence of vast mature NFTs deposits as are typically observed in human AD. In one study, cytoplasmic deposits of phosphorylated TAU (pTAUThr181) were detected in the prefrontal cortex, but no NFTs were observed (Pugliese et al., 2006). Smolek et al. (2016) detected increased presence of phosphorylated TAU protein (pTAU) in synaptosomes of demented dogs. This could suggest that dementia in dogs might be partially caused by the weakening of the synaptic function, caused by pTAU, and not by the toxic effects of NFTs. This is further supported by the increase in TAU hyperphosphorylation in individual cortical neurons and by pTAU subcellular distribution shift from perinuclear to granular cytoplasmic and nuclear, which correlates with dog’s age (Pugliese et al., 2006). Expression of pTAUSer396 and accumulation of ubiquitin were also significantly increased in the parietal cortex and dorsal part of the hippocampus in old dogs when compared to expression in humans (Pugliese et al., 2006; Yu et al., 2011). Specifically, pTAUSer396 expressing astrocytes and neurons with co-localization of pTAUSer396 and ubiquitin were also observed in the parietal cortices and hippocampi of dogs with CCD (Yu et al., 2011). However, cytoplasmic aggregates of normally predominately nuclear proteins, TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS), which are strongly associated with frontotemporal dementia and amyotrophic lateral sclerosis in human patients, were not detected in the canine brain with CCD (Smolek et al., 2016).