PMC:6582309 / 9798-29051 JSONTXT

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Neuropathology in the Brain Parenchyma\nThe most prominent neuropathological signs of AD are accumulation of Aβ in a form of extracellular plaques in the brain parenchyma and also in the walls of blood vessels (cerebral amyloid angiopathy, CAA), and abnormally phosphorylated protein TAU that accumulates in NFTs (Braak and Braak, 1991; Nelson et al., 2012). These pathological features are believed to cause cognitive and behavioral changes. The amino acid sequence of APP and of the enzymes involved in the processing of Aβ peptides from APP, are highly homologous between humans and dogs (Johnstone et al., 1991; Sarasa and Pesini, 2009; Sarasa et al., 2010). Major canine APP isoforms are APP-770, APP-751, APP-714, and APP-695 (Sarasa et al., 2010). The alignment of the longest canine amyloid-beta precursor protein isoform (APP-770) sequence with protein sequence of human amyloid-beta precursor protein show 96.9% amino acid identity and 98.3% similarity (Figure 1A), making them almost identical. The expression patterns of canine APP isoforms are almost similar to the patterns previously detected for human APP isoforms (Yasojima et al., 2001; Sarasa et al., 2010). APP is a single-pass transmembrane protein with a large extracellular domain and a short cytoplasmic tail. The domain structure of APP-770 is shown in Figure 1B, the neuronal isoform APP-695 lacks the KPI domain (Müller et al., 2017). In contrary to APP, there is a difference in the TAU protein sequence between dogs and humans. Figure 1C shows the longest TAU isoform alignment between dog and human protein sequences with 84% similarity. Interestingly, the four microtubule-binding regions (4R) and the C-terminal regions (Figures 1C,D) are identical.\nFIGURE 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. Amyloid-β was found to be present in the form of insoluble plaques in the area of the cerebral cortex in humans and dogs, and cognitive impairment in elderly dogs was in some studies strongly associated with the accumulation of Aβ in the brain (Cummings et al., 1993; Cummings and Cotman, 1995; Pugliese et al., 2006; Rofina et al., 2006; Barnes et al., 2016). However, in two other studies there was no significant correlation between the amount of Aβ brain load and CCD symptoms (Chambers et al., 2011; Ozawa et al., 2016) so the clear connection between Aβ load in the brain and clinical signs of CCD has not been firmly established yet. Although Aβ plaques are generally detected as extracellular deposits of diffuse and neuritic plaques in humans and dogs, some studies also reported the presence of Aβ deposits inside individual neurons in the canine brain (Cummings et al., 1993; Yu et al., 2011). Similarly, intraneuronal Aβ accumulation in human AD brains has been reported by many groups (reviewed in detail by Gouras et al., 2010).\nIn dogs, formation and maturation of Aβ deposits was observed by immunostaining throughout the canine cortical gray matter layers in a four-stage distribution, which is also characteristic for human AD, and this, according to some studies, correlates with the severity of cognitive deficit in the dog (Bosch et al., 2012) and varies as a function of age and size (weight) in companion dogs (Rofina et al., 2006; Schmidt et al., 2015). The Aβ load was higher in small and medium size dogs, which can be explained by the longer life span of smaller dogs and thus longer time necessary to accumulate these deposits (Schmidt et al., 2015). Most of the studies, on CCD brains, were made on geriatric dogs of different breeds and sizes, hence in this review the pathology is mainly described without further specifications of individual dogs characteristics. The canine prefrontal cortex is normally the site of disease onset (Figure 2), which spreads progressively to the parietal, entorhinal and occipital cortices, and lesions in certain brain regions correlate with certain behavioral deficits, as shown in Table 1. In separate studies amyloid plaques of mainly diffuse type were detected in several regions of canine brain, in the frontal and temporal cortex (Ishihara et al., 1991; Colle et al., 2000; Pugliese et al., 2006; Schmidt et al., 2015; Ozawa et al., 2016; Schütt et al., 2016; Smolek et al., 2016), in entorhinal cortex and hippocampus (Cummings et al., 1993; Colle et al., 2000; Yu et al., 2011; Schmidt et al., 2015; Borghys et al., 2017) and parietal cortex (Yu et al., 2011). Hippocampal deposits of a subspecies of pyroglutamyl Aβ, the highly neurotoxic pE3AA, were also detected in demented dogs (Schmidt et al., 2015). These plaques were more abundant in small and medium dogs (Schmidt et al., 2015). Studies further suggest that earlier assembly states of Aβ, such as oligomers and protofibrils, may be neurotoxic in the dog’s brain (Head et al., 2010). The levels of Aβ soluble oligomers in the CSF correlated inversely with Aβ load in the CCD affected beagle brains (Head et al., 2010). Precipitates from the CSF of demented Samoyed dog with CCD acted highly neurotoxic in in vitro tests and were more neurotoxic than the synthetic oligomeric and fibrillary forms of Aβ (Rusbridge et al., 2018).\nFIGURE 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.\nTABLE 1 Affected brain regions and underlying cognitive deficits in dogs.\nBrain region Pathology Cognitive decline References\nPrefrontal cortex Aβ Executive function, behavioral changes [cognitive performance, loss of previously learned behaviors (e.g., house soiling)], motor skills, attention, emotions and impulse control (fearfulness, aggression, stereotypic pacing or circling) Bosch et al.,2012\nFrontal cortex Aβ Changes in executive functions (inhibitory control and complex working memory) Ishihara et al., 1991; Schmidt et al., 2015; Smolek et al.,2016\nParietal cortex Aβ Sensory association, learning and memory Yu et al., 2011; Nešić et al.,2017\nEntorhinal cortex Aβ, NFTs* Visual learning, memory Schmidt et al., 2015; Smolek et al.,2016\nOccipital cortex Aβ Learning and memory (visual association area, visual cortex) Martin et al.,2011\nTemporal cortex Aβ, NFTs* Visual memory (facial recognition), emotions Smolek et al.,2016\nHippocampus Aβ, NFTs* Changes in sleep–wake cycles, appetite control, complex working memory Colle et al., 2000; Pugliese et al., 2006; Yu et al., 2011; Schmidt et al., 2015; Smolek et al.,2016\nCerebral cortex (not further specified) Aβ Disorientation, decrease in social interactions, changes in sleep–wake cycles, loss of prior housetraining, increased anxiety, changes in level of activity Colle et al., 2000; Pugliese et al., 2006; Yu et al.,2011\nCerebral capillaries and arteries Aβ - CAA Lower perceptual speed and episodic memory Ishihara et al., 1991; Colle et al., 2000; Yu et al.,2011\nMeningeal blood vessels Aβ - CAA Ishihara et al., 1991; Borràs et al., 1999; Colle et al., 2000; Yu et al., 2011; Nešić et al.,2017\n*NTFs are rarely detected in CCD. Besides Aβ plaques, recruitment and activation of astrocytes and microglial cells has been noticed in dogs with CCD (astrocytosis, microgliosis) (Smolek et al., 2016; Rusbridge et al., 2018) along with astrocyte hypertrophy (Borràs et al., 1999). Furthermore, the levels of pathological Aβ in the canine prefrontal cortex were positively correlated with age but neither with the severity of cognitive deficits (Gómez-Pinedo et al., 2016) nor the neuronal cell loss (Cummings et al., 1993). Neprilysin (NEP) mRNA, coding for a pivotal Aβ-degrading protein, was poorly expressed in the prefrontal cortex of aged dogs with CCD (Canudas et al., 2014), similar to human AD brain, where areas with higher Aβ aggregation express lower levels of NEP (Reilly, 2001).\nAged dogs with cognitive impairment exhibit degeneration of noradrenergic neurons, which correlates with higher levels of Aβ deposits in the prefrontal cortex (Insua et al., 2010). Likewise, in human AD, locus coeruleus degeneration and loss of cortical noradrenergic neurons occurs already at early stage (Kelly et al., 2017). The activity of the canine cholinergic system also declines with age (Araujo et al., 2005b). Number of basal forebrain cholinergic neurons was significantly reduced in aged cognitively impaired dogs in comparison to aged cognitive unimpaired and young dogs, but unlike for noradrenergic neurons, this reduction of cholinergic neurons did not correlate with the extent of Aβ cortical load (Insua et al., 2012). As in CCD, cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are usually lost in AD (Whitehouse et al., 1981). In human patients, the cholinergic neurons appear most vulnerable to Aβ pathology, followed by glutamatergic and GABAergic neurons (Bell et al., 2006). The synaptic loss correlates with the disease progression and destruction of cholinergic neurons contributes to memory and attention deficits in AD (Terry et al., 1991). These alterations in neurotransmitter systems, with reduced neuronal and synaptic function have also been observed in dogs (Landsberg et al., 2012) and result in clinical symptoms of CCD. The employment of the canine model to examine the effect of the cholinesterase inhibitors in treatment of CCD is described in details under “Treatment and drug development”.\nTAU 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).\nNeurodegenerative diseases occur spontaneously in other domestic animals, especially in cats (Chambers et al., 2015), although brain pathology in these other species is much less studied. In the hippocampi of naturally aged domestic cats, Aβ accumulation, NFTs formation and neuronal loss were observed (Chambers et al., 2015) and this might contribute to cognitive decline in this species, although this has not yet been firmly established. Cognitive deficit may occur in the horse, as clinical signs similar to cognitive impairment have been observed, but no detailed studies focusing on age-related neurologic aberrances have been conducted so far. In one study, TAU protein was shown to be present in equine hippocampal neurons, but no NFTs were detected (Capucchio et al., 2010). Some horses develop equine motor neuron disease, but none have been associated with pathological accumulation of dementia related proteins (El-Assaad et al., 2012; Youssef et al., 2016). Interestingly, a recent study negated the belief that abnormally behaving stereotypic horses (Equus caballus) are cognitively impaired (Briefer Freymond et al., 2018).\nNeurodegenerative diseases most likely occur in many other mammalian species, but there are very limited reports about these. The reports are focusing on the presence of Aβ deposits and phosphorylated TAU and/or NFTs, which are detected post mortem, not describing the cognitive deficit, this is of course more difficult to observe in wild life animals or in this aspect less characterized species. Diffuse deposits of Aβ were observed in the parietal cortex of dolphins and more compact senile plaques in their cerebellum (Di Guardo, 2018). Sheep and goats (Braak et al., 1994; Nelson et al., 1994; Nelson and Saper, 1995), cheetah (Serizawa et al., 2012), bison (Härtig et al., 2000, 2001), bears (Cork et al., 1988) and most species of nonhuman primates (Schultz et al., 2000a, b; Rosen et al., 2008; Oikawa et al., 2010; Perez et al., 2013, 2016; Rodriguez-Callejas et al., 2016; Reid et al., 2017) also develop amyloid plaques and/or harbor phosphorylated TAU laden neurons, but most of them do not have NFTs present in their central nervous systems (as reviewed in Youssef et al., 2016). However, AT8-immunostained pTAUSer202 and pTAUThr205 were found in the brains of brown lemur, rhesus monkey, baboons, rabbit, guanaco, and bison (Härtig et al., 2000). Furthermore, NFTs were revealed by Gallyas staining in aged bison (Härtig et al., 2001).\nThere have been speculations on the reasons for the lack of NFTs in the canine brain and in the brains of other animals (Kuroki et al., 1997; Youssef et al., 2016). First possibility is the dissimilarity between canine TAU protein sequence in comparison to human’s. Secondly, the lifespan of dogs might be too short to develop NFTs, as Aβ deposition precedes NTFs formation. Thirdly, although the amyloid protein sequence is highly conserved between species, its N-terminal part is not, which might influence TAU phosphorylation and its subsequent aggregation into NFTs. Therefore, it seems that only humans develop the full blown AD pathology with amyloid plaques, NFTs and dementia. There have been few reports of possible AD in aged great apes (Rosen et al., 2008; Perez et al., 2013, 2016), although also in these the TAU pathology was very limited. Several reasons for this exceptional vulnerability of humans to develop AD have been proposed (Arendt et al., 2017; Walker and Jucker, 2017). Predisposition to develop AD might arise as early as during embryonic development over the period of neurogenesis, this was inferred from the modular deposition of AD related cerebral deposits which mirrors the formation and migration of neurons and on a larger scale development of brain regions (Arendt et al., 2017). In humans, the relative brain size is much larger than in any other animal and this expansion is due to longer duration of brain development as well as higher number of neuronal progenitor cell division cycles, the latter giving rise to genomic aberrations, which in turn can be the origin of AD (Arendt et al., 2017). Furthermore, the neurons display genomic mosaicism, which was detected in neurons of approximately 10% of normally aged people. These neurons were shown to preferentially undergo apoptosis in AD (Arendt et al., 2010). The extent of neuronal genomic mosaicism is brain region specific and correlates with differential vulnerability to neurofibrillary pathology (Arendt et al., 2015). Moreover, the pathological TAU conversion might commence as early as in children (Braak and Del Tredici, 2012), although it has not been firmly established if these processes are transient in nature. The canine model would therefore serve as an accessible and suitable model to further delineate why, except for humans, are other species less susceptible to develop tauopathies."}

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Neuropathology in the Brain Parenchyma\nThe most prominent neuropathological signs of AD are accumulation of Aβ in a form of extracellular plaques in the brain parenchyma and also in the walls of blood vessels (cerebral amyloid angiopathy, CAA), and abnormally phosphorylated protein TAU that accumulates in NFTs (Braak and Braak, 1991; Nelson et al., 2012). These pathological features are believed to cause cognitive and behavioral changes. The amino acid sequence of APP and of the enzymes involved in the processing of Aβ peptides from APP, are highly homologous between humans and dogs (Johnstone et al., 1991; Sarasa and Pesini, 2009; Sarasa et al., 2010). Major canine APP isoforms are APP-770, APP-751, APP-714, and APP-695 (Sarasa et al., 2010). The alignment of the longest canine amyloid-beta precursor protein isoform (APP-770) sequence with protein sequence of human amyloid-beta precursor protein show 96.9% amino acid identity and 98.3% similarity (Figure 1A), making them almost identical. The expression patterns of canine APP isoforms are almost similar to the patterns previously detected for human APP isoforms (Yasojima et al., 2001; Sarasa et al., 2010). APP is a single-pass transmembrane protein with a large extracellular domain and a short cytoplasmic tail. The domain structure of APP-770 is shown in Figure 1B, the neuronal isoform APP-695 lacks the KPI domain (Müller et al., 2017). In contrary to APP, there is a difference in the TAU protein sequence between dogs and humans. Figure 1C shows the longest TAU isoform alignment between dog and human protein sequences with 84% similarity. Interestingly, the four microtubule-binding regions (4R) and the C-terminal regions (Figures 1C,D) are identical.\nFIGURE 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. Amyloid-β was found to be present in the form of insoluble plaques in the area of the cerebral cortex in humans and dogs, and cognitive impairment in elderly dogs was in some studies strongly associated with the accumulation of Aβ in the brain (Cummings et al., 1993; Cummings and Cotman, 1995; Pugliese et al., 2006; Rofina et al., 2006; Barnes et al., 2016). However, in two other studies there was no significant correlation between the amount of Aβ brain load and CCD symptoms (Chambers et al., 2011; Ozawa et al., 2016) so the clear connection between Aβ load in the brain and clinical signs of CCD has not been firmly established yet. Although Aβ plaques are generally detected as extracellular deposits of diffuse and neuritic plaques in humans and dogs, some studies also reported the presence of Aβ deposits inside individual neurons in the canine brain (Cummings et al., 1993; Yu et al., 2011). Similarly, intraneuronal Aβ accumulation in human AD brains has been reported by many groups (reviewed in detail by Gouras et al., 2010).\nIn dogs, formation and maturation of Aβ deposits was observed by immunostaining throughout the canine cortical gray matter layers in a four-stage distribution, which is also characteristic for human AD, and this, according to some studies, correlates with the severity of cognitive deficit in the dog (Bosch et al., 2012) and varies as a function of age and size (weight) in companion dogs (Rofina et al., 2006; Schmidt et al., 2015). The Aβ load was higher in small and medium size dogs, which can be explained by the longer life span of smaller dogs and thus longer time necessary to accumulate these deposits (Schmidt et al., 2015). Most of the studies, on CCD brains, were made on geriatric dogs of different breeds and sizes, hence in this review the pathology is mainly described without further specifications of individual dogs characteristics. The canine prefrontal cortex is normally the site of disease onset (Figure 2), which spreads progressively to the parietal, entorhinal and occipital cortices, and lesions in certain brain regions correlate with certain behavioral deficits, as shown in Table 1. In separate studies amyloid plaques of mainly diffuse type were detected in several regions of canine brain, in the frontal and temporal cortex (Ishihara et al., 1991; Colle et al., 2000; Pugliese et al., 2006; Schmidt et al., 2015; Ozawa et al., 2016; Schütt et al., 2016; Smolek et al., 2016), in entorhinal cortex and hippocampus (Cummings et al., 1993; Colle et al., 2000; Yu et al., 2011; Schmidt et al., 2015; Borghys et al., 2017) and parietal cortex (Yu et al., 2011). Hippocampal deposits of a subspecies of pyroglutamyl Aβ, the highly neurotoxic pE3AA, were also detected in demented dogs (Schmidt et al., 2015). These plaques were more abundant in small and medium dogs (Schmidt et al., 2015). Studies further suggest that earlier assembly states of Aβ, such as oligomers and protofibrils, may be neurotoxic in the dog’s brain (Head et al., 2010). The levels of Aβ soluble oligomers in the CSF correlated inversely with Aβ load in the CCD affected beagle brains (Head et al., 2010). Precipitates from the CSF of demented Samoyed dog with CCD acted highly neurotoxic in in vitro tests and were more neurotoxic than the synthetic oligomeric and fibrillary forms of Aβ (Rusbridge et al., 2018).\nFIGURE 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.\nTABLE 1 Affected brain regions and underlying cognitive deficits in dogs.\nBrain region Pathology Cognitive decline References\nPrefrontal cortex Aβ Executive function, behavioral changes [cognitive performance, loss of previously learned behaviors (e.g., house soiling)], motor skills, attention, emotions and impulse control (fearfulness, aggression, stereotypic pacing or circling) Bosch et al.,2012\nFrontal cortex Aβ Changes in executive functions (inhibitory control and complex working memory) Ishihara et al., 1991; Schmidt et al., 2015; Smolek et al.,2016\nParietal cortex Aβ Sensory association, learning and memory Yu et al., 2011; Nešić et al.,2017\nEntorhinal cortex Aβ, NFTs* Visual learning, memory Schmidt et al., 2015; Smolek et al.,2016\nOccipital cortex Aβ Learning and memory (visual association area, visual cortex) Martin et al.,2011\nTemporal cortex Aβ, NFTs* Visual memory (facial recognition), emotions Smolek et al.,2016\nHippocampus Aβ, NFTs* Changes in sleep–wake cycles, appetite control, complex working memory Colle et al., 2000; Pugliese et al., 2006; Yu et al., 2011; Schmidt et al., 2015; Smolek et al.,2016\nCerebral cortex (not further specified) Aβ Disorientation, decrease in social interactions, changes in sleep–wake cycles, loss of prior housetraining, increased anxiety, changes in level of activity Colle et al., 2000; Pugliese et al., 2006; Yu et al.,2011\nCerebral capillaries and arteries Aβ - CAA Lower perceptual speed and episodic memory Ishihara et al., 1991; Colle et al., 2000; Yu et al.,2011\nMeningeal blood vessels Aβ - CAA Ishihara et al., 1991; Borràs et al., 1999; Colle et al., 2000; Yu et al., 2011; Nešić et al.,2017\n*NTFs are rarely detected in CCD. Besides Aβ plaques, recruitment and activation of astrocytes and microglial cells has been noticed in dogs with CCD (astrocytosis, microgliosis) (Smolek et al., 2016; Rusbridge et al., 2018) along with astrocyte hypertrophy (Borràs et al., 1999). Furthermore, the levels of pathological Aβ in the canine prefrontal cortex were positively correlated with age but neither with the severity of cognitive deficits (Gómez-Pinedo et al., 2016) nor the neuronal cell loss (Cummings et al., 1993). Neprilysin (NEP) mRNA, coding for a pivotal Aβ-degrading protein, was poorly expressed in the prefrontal cortex of aged dogs with CCD (Canudas et al., 2014), similar to human AD brain, where areas with higher Aβ aggregation express lower levels of NEP (Reilly, 2001).\nAged dogs with cognitive impairment exhibit degeneration of noradrenergic neurons, which correlates with higher levels of Aβ deposits in the prefrontal cortex (Insua et al., 2010). Likewise, in human AD, locus coeruleus degeneration and loss of cortical noradrenergic neurons occurs already at early stage (Kelly et al., 2017). The activity of the canine cholinergic system also declines with age (Araujo et al., 2005b). Number of basal forebrain cholinergic neurons was significantly reduced in aged cognitively impaired dogs in comparison to aged cognitive unimpaired and young dogs, but unlike for noradrenergic neurons, this reduction of cholinergic neurons did not correlate with the extent of Aβ cortical load (Insua et al., 2012). As in CCD, cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are usually lost in AD (Whitehouse et al., 1981). In human patients, the cholinergic neurons appear most vulnerable to Aβ pathology, followed by glutamatergic and GABAergic neurons (Bell et al., 2006). The synaptic loss correlates with the disease progression and destruction of cholinergic neurons contributes to memory and attention deficits in AD (Terry et al., 1991). These alterations in neurotransmitter systems, with reduced neuronal and synaptic function have also been observed in dogs (Landsberg et al., 2012) and result in clinical symptoms of CCD. The employment of the canine model to examine the effect of the cholinesterase inhibitors in treatment of CCD is described in details under “Treatment and drug development”.\nTAU 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).\nNeurodegenerative diseases occur spontaneously in other domestic animals, especially in cats (Chambers et al., 2015), although brain pathology in these other species is much less studied. In the hippocampi of naturally aged domestic cats, Aβ accumulation, NFTs formation and neuronal loss were observed (Chambers et al., 2015) and this might contribute to cognitive decline in this species, although this has not yet been firmly established. Cognitive deficit may occur in the horse, as clinical signs similar to cognitive impairment have been observed, but no detailed studies focusing on age-related neurologic aberrances have been conducted so far. In one study, TAU protein was shown to be present in equine hippocampal neurons, but no NFTs were detected (Capucchio et al., 2010). Some horses develop equine motor neuron disease, but none have been associated with pathological accumulation of dementia related proteins (El-Assaad et al., 2012; Youssef et al., 2016). Interestingly, a recent study negated the belief that abnormally behaving stereotypic horses (Equus caballus) are cognitively impaired (Briefer Freymond et al., 2018).\nNeurodegenerative diseases most likely occur in many other mammalian species, but there are very limited reports about these. The reports are focusing on the presence of Aβ deposits and phosphorylated TAU and/or NFTs, which are detected post mortem, not describing the cognitive deficit, this is of course more difficult to observe in wild life animals or in this aspect less characterized species. Diffuse deposits of Aβ were observed in the parietal cortex of dolphins and more compact senile plaques in their cerebellum (Di Guardo, 2018). Sheep and goats (Braak et al., 1994; Nelson et al., 1994; Nelson and Saper, 1995), cheetah (Serizawa et al., 2012), bison (Härtig et al., 2000, 2001), bears (Cork et al., 1988) and most species of nonhuman primates (Schultz et al., 2000a, b; Rosen et al., 2008; Oikawa et al., 2010; Perez et al., 2013, 2016; Rodriguez-Callejas et al., 2016; Reid et al., 2017) also develop amyloid plaques and/or harbor phosphorylated TAU laden neurons, but most of them do not have NFTs present in their central nervous systems (as reviewed in Youssef et al., 2016). However, AT8-immunostained pTAUSer202 and pTAUThr205 were found in the brains of brown lemur, rhesus monkey, baboons, rabbit, guanaco, and bison (Härtig et al., 2000). Furthermore, NFTs were revealed by Gallyas staining in aged bison (Härtig et al., 2001).\nThere have been speculations on the reasons for the lack of NFTs in the canine brain and in the brains of other animals (Kuroki et al., 1997; Youssef et al., 2016). First possibility is the dissimilarity between canine TAU protein sequence in comparison to human’s. Secondly, the lifespan of dogs might be too short to develop NFTs, as Aβ deposition precedes NTFs formation. Thirdly, although the amyloid protein sequence is highly conserved between species, its N-terminal part is not, which might influence TAU phosphorylation and its subsequent aggregation into NFTs. Therefore, it seems that only humans develop the full blown AD pathology with amyloid plaques, NFTs and dementia. There have been few reports of possible AD in aged great apes (Rosen et al., 2008; Perez et al., 2013, 2016), although also in these the TAU pathology was very limited. Several reasons for this exceptional vulnerability of humans to develop AD have been proposed (Arendt et al., 2017; Walker and Jucker, 2017). Predisposition to develop AD might arise as early as during embryonic development over the period of neurogenesis, this was inferred from the modular deposition of AD related cerebral deposits which mirrors the formation and migration of neurons and on a larger scale development of brain regions (Arendt et al., 2017). In humans, the relative brain size is much larger than in any other animal and this expansion is due to longer duration of brain development as well as higher number of neuronal progenitor cell division cycles, the latter giving rise to genomic aberrations, which in turn can be the origin of AD (Arendt et al., 2017). Furthermore, the neurons display genomic mosaicism, which was detected in neurons of approximately 10% of normally aged people. These neurons were shown to preferentially undergo apoptosis in AD (Arendt et al., 2010). The extent of neuronal genomic mosaicism is brain region specific and correlates with differential vulnerability to neurofibrillary pathology (Arendt et al., 2015). Moreover, the pathological TAU conversion might commence as early as in children (Braak and Del Tredici, 2012), although it has not been firmly established if these processes are transient in nature. The canine model would therefore serve as an accessible and suitable model to further delineate why, except for humans, are other species less susceptible to develop tauopathies."}