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Supplement: Waltham International Symposium

Aspects of Neurodegeneration in the Canine Brain

School of Biomedical Sciences, University of Nottingham, Medical School, Queens Medical Centre, Nottingham, NG7 ZUH UK

³To whom correspondence should be addressed. E-mail: mbxad{at}nottingham.ac.uk.

	ABSTRACT

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The process of neurodegeneration displays some common morphological characteristics, most of which are jointly observed in the brains of most mammalian species. In the canine brain, neurodegeneration is frequently typified by an extensive ß-amyloid (Aß) deposition (mainly of the C-terminal Aß1–42 form) within the neurones and at the synaptic regions, in the early stages of the process. These deposits subsequently appear to give rise to the formation of senile plaques of the diffuse (non-ß-sheet) subtype, which tend to develop spontaneously but rarely proceed to form neuritic plaques. Additional features accompanying neurodegeneration include accumulations of the "aging pigment," lipofuscin, intraneuronal changes in the cytoskeleton, vascular changes in the cerebrum, cortical cerebral atrophy, enlargement of the ventricles and increased concentration of oxidative stress markers, many of which are perceived as cardinal features of extensive dysfunction in the protein turnover network. The involvement of ubiquitin is discrete but consistent in many of these molecular structures and seems to account for some critical aspects of the associated neuropathology. Irrespective of these, though, the degenerated canine brain seems to be devoid of neurofibrillary tangle formation, a manifestation commonly observed in the brain of both aged (cognitively normal) and Alzheimer-affected human subjects. The fact that canines exhibit clear symptoms of an age-related cognitive decline pertains to the concept of Aß playing a central role in age-related cognitive dysfunction and neurodegeneration.

KEY WORDS: • ß-amyloid (Aß) • neurodegeneration • aging

A major part of today’s research in neuropathology and cognitive function of the brain has been largely dedicated to the elucidation of the molecular events involved in ß-amyloid accumulation, senile plaque formation and the generation of neurofibrillary tangles (NFTs) in the intracellular space of neurons. Extensive studies have also been performed at the macroscopic level of neurodegeneration, indicating the anatomical and histological changes accompanying the process. A significant amount of this research has utilized the canine model as a subject of study, providing valuable insights to the mechanisms implicated and the pathogenic factors involved. In fact, the canine model is proving more and more to constitute an indispensable means of study of the process of neurodegeneration because it has allowed the theoretic approach of the problem from entirely new perspectives, that might not lie so far from the full picture, after all.

	NEUROPATHOLOGICAL HALLMARKS OF THE DEGENERATED CANINE BRAIN

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ß-Amyloid peptide

Perhaps the most consistently observed lesion of the neurodegenerated canine brain pertains to senile plaques and the diffuse deposits of ß-amyloid (Aß) peptide. These features have long been regarded as the main neuropathological features of the Alzheimer-affected brain as well as the aged, nondemented one. Their presence in the canine, in addition to the well-observed cognitive decline of canines as a function of age (1), has led to inferences that they might be the major factor implicated in neurodegeneration.

Diffuse plaques: the predominant type of lesion in the canine brain

Senile plaques are extracellular molecular aggregates of presenilin 1 (PS1), apolipoprotein E (apoE) and ß-amyloid peptide (Aß), of which the latter is the primary constituent (2). Plaques are categorized into three major subtypes, depending on their stage of progress: diffuse (non-ß-sheet), primitive (ß-sheet lacking a central core of amyloid) and neuritic (ß-sheet containing a central core of amyloid and extensive reactive astroglia, in canines). It is believed that the progression of plaque formation proceeds through specific identifiable stages (i.e., in the succession mentioned above), from diffuse to the neuritic (Gallyas-A4 or Congo red stain positive) subtype, which also signifies end-stage Alzheimer’s disease (AD) in humans. Extensive immunohistochemical and fluorescence staining analyses demonstrate that the plaque most consistently observed in the canine brain is of the diffuse subtype (3–5), although occasional occurrence of mature (primitive or neuritic) plaques cannot be excluded, given that some studies in the past have provided undisputed, though rare, evidence of Congo red staining plaques in canine brain tissue (6). Despite these findings, the view that Aß within the diffuse canine plaque is generally not in the ß-pleated-sheet conformation (and thus Congo and thioflavine negative) is firmly established.

The plaque subtypes found in the degenerated canine brain are, as in humans, not the same in all regions. Different sites might show a predilection for specific plaque formation giving rise to an uneven distribution of plaques, in quantitative terms. The distribution is uneven both at the immediate cellular level and the cerebrocortical surface level. In the former instance, a site that has been known to selectively accumulate Aß deposits is the axonal synaptic terminal fields of neurons (7), whereas the uneven cortical distribution of plaques is exemplified by studies showing the prefrontal cortex as the commonest site of onset of plaque formation in the canine (8), followed chronologically by the parietal, entorhinal and finally the occipital cortices (Fig. 1) (9). It is the insult in these regions that is considered to account for the observed cognitive decline of the neurodegenerated brain. In support of this view, some studies have produced evidence demonstrating that the surface area containing Aß deposition (extension index) actually parallels the decline in cognitive performance of aged canines (10).

View larger version (46K): [in this window] [in a new window]   FIGURE 1 A schematic representation of the pattern of Aß deposition in four different brain regions in aging dogs. Stage 1 is characterized by Aß deposition only in the prefrontal cortex. Stage 2 shows that at least two cortical regions are affected by Aß deposition. Stage 3 is defined as extensive Aß deposition in many cortical regions and with maximal prefrontal deposition. Aß seems to be deposited first in the prefrontal cortex, then in the parietal cortex, followed by the entorhinal cortex and finally in the occipital lobe. The key at the top right corner indicates the range of Aß loads represented by each color: light gray, 0–5% Aß deposition; dark gray, 5–15% Aß deposition; black, 15–35% Aß deposition. [Reprinted from Head et al. (9) with permission from Elsevier Science.]

Another notable feature of the diffuse canine plaques relates to the fact that their spread and number often equals or exceeds that seen even in the most severe cases of AD in humans, and yet the canine’s cognitive decline as a result of neurodegeneration can only be regarded as pre-Alzheimer’s stage. What is more, the plaques themselves tend to develop spontaneously and are usually far larger than the ones observed in the human AD brain(13). An additional differentiating point from the situation met in humans pertains to the presence of glial reactivity within the plaques: unlike the high level of reactive microglia within the AD neuritic plaques, diffuse canine plaques are devoid of any infiltrating hyperactive glia; instead, they are more closely associated with astrocyte reactivity (3). This situation, however, is quickly altered if the plaque Aß is converted to the ß-pleated-sheet formation (17). Finally, a paradox is associated with the cellular integrity of the intraplaque neurons of the canine brain: despite the view that amyloid plaques are the destructive agents of neuronal cells, the latter are invariably found intact, embedded in the amyloid mass. This can be explained by the finding that Aß exerts its neurotoxic effects only when found in its aggregated ß-pleated-sheet form, whereas it is neurotrophic when it is in solution (18).

Added together, these findings suggest a vitally important role of Aß in the neurodegeneration of the canine brain and provide insights for the analogous process in human brain, whose neurodegeneration might just be the end result of what is observed in its canine counterpart.

Intraneuronal changes in the cytoskeleton

Despite the common pathology in the case of the ß-amyloid peptide, canine and human brains are markedly dissimilar as far as development of NFTs is concerned. NFTs are, along with Aß, the principal hallmarks of AD in humans, often indicating end-stage pathogenesis of the disease. Yet, detailed studies on the neurodegenerated canine brain have failed repeatedly to demonstrate the presence of these structures in canine neurons (4,13,19). It is therefore now an unequivocal belief that the process of neurodegeneration in canines does not involve NFT formation. A rare finding, though, was produced from a recent study utilizing monoclonal antibody technology to reveal NFTs in the brains of aged canines (4). In this study three different antibodies raised against tau, the constituent protein of NFTs, were used, one of which gave positive results revealing a punctuate pattern of NFT dispersal in sections of canine brain. Previous attempts again with the aid of immunocytochemistry, targeting paired helical filaments (PHFs), pan-neuronal (found in all neurones) neurofilament components (SMI-310) and phosphorylated tau protein, have all proved unfruitful. It appears that the only verified cytoskeletal abnormality observed in the neurodegenerated canine brain is associated with a certain degree of abnormal axonal sprouting in the brain neurons, especially of the dendrites.

Still, there is increasing concern about the role of ubiquitin (Ub) in relation to NFTs. Although NFTs are almost invariably absent from the canine brain, there have been reports of ubiquitinated aggregates in the myelinated axons of canine neurons, which form granular dense bodies with increasing age (20). In human AD patients approximately 30% of the NFT-associated tau is found polyubiquitinated (21). Dementia with Lewy Bodies (DLB), the second most common neurodegenerating condition in humans, has also been found to exhibit a similar neuropathology. The Lewy body, the neuropathological hallmark of this condition and also of Parkinson’s disease (PD), is an intracellular inclusion filled with ubiquitinated proteins, most of which exhibit a filamentous structure. Therefore, in the light of new discoveries that reveal an increasingly intimate relationship of ubiquitin with NFTs and their constituent hyperphosphorylated tau (21), it is sensible to consider the possibility that neurodegeneration in the canine brain might after all share some common mechanisms with those observed in the human one.

Other cellular features of the neurodegenerated canine brain

The neurodegenerative characteristics of the canine brain are not only restricted to Aß and NFT formation. Although the aforementioned are considered to be the major hallmarks, a wide array of intracellular changes can also be observed in degenerated canine subjects, encompassing the genomic integrity of neurons, the operation of signaling cascades and the redox state of the intracellular environment. The latter is of particular importance, given that the oxidative stress component of cellular physiology is increasingly found to be implicated in the pathogenesis of many diseased states and abnormal conditions ranging from neurodegeneration and AD pathogenesis to aging and carcinogenesis. The aged canine brain has been found to exhibit high levels of oxidative stress, as well. Recent studies demonstrate the presence of oxidative stress markers, like 4-hydroxynonenal (HNE), in high concentrations detected by immunohistochemical techniques in the amyloid deposits, vascular wall areas, perivascular spaces as well as within some neurons in aged canine brains (4). Complemented by observations derived from pharmacological studies focusing on the modification of endogenous antioxidant enzymes, the concept of oxidative stress-associated neurodegeneration is further reinforced. More specifically, it has been shown that deprenyl (a monoamine oxidase B inhibitor) administration over a certain period of time appears to induce catalase (CAT) and superoxide dismutase (SOD) activities selectively in canine brain dopaminergic neurons, conferring neuropreotection and prolonged cell survival (22). Taking into account the large oxidative component of AD pathology in humans, these findings indicate that oxidative stress might play a crucial part in the process of neurodegeneration that had until recently been underestimated.

Genomic integrity is also known to be compromised during neurodegeneration in the canine. In situ end-labeling of nuclear DNA fragmentation (TUNEL) experiments indicate a positive correlation between DNA damage and the extent of amyloid deposition in the aged canine brain (23). It is suggested that the extent of DNA damage sustained might not just be an experimental artifact of this type of studies but a cellular manifestation directly related to Aß deposition and perhaps the progression of neurodgeneration. TUNEL labeling studies also reveal that the observed DNA fragmentation is not a consequence of operating apoptotic mechanisms (24). It is noteworthy that some degree of DNA fragmentation has been reported in both canines and humans in normal aging as well as in certain neurodgenerative disorders, although that, too, is rarely accompanied by any apoptotic morphology.

Changes in the intracellular signaling pathways in the neurodegenerated canine brain include a variety of receptors, proteins with intrinsic kinase or phosphatase activity and transcription factors. A notable recent finding pertaining to the neurotrophic signal cascades relates to the brain-derived neurotrophic factor (BDNF). Cyclic AMP-responsive element binding protein (CREB) is one of the transcription factors that participate in the regulation of the BDNF gene. Aß has been found to decrease the phosphorylation state of CREB, thereby inactivating it and causing a downregulation of the BDNF gene that can lead up to a 31% decrease in BDNF levels (25). The concomitant neuronal loss by neurotrophic factor deprivation is hypothesized to account, at least in part, for the observed pathology of neurodegeneration in the canine as well as in the human brain.

A final point that should also be addressed involves the role of advanced end-glycation products (AGEs) and their association to neuropathology in the canine. AGEs are thought to be associated with the pathogenesis of AD and normal aging in humans. They accumulate preferentially in Aß plaques and NFTs, as well as in other sites within neurons, in an age-dependent manner. Immunohistochemical examinations of canine brain tissue have demonstrated that AGE granular accumulations develop within neurons with advancing age (26). These granules seem to contain the protein, but not the lipid components, of lipofuscin, the yellowish autofluorescent pigment that has long been known to exhibit a striking correlation with brain tissue aging—an observation that has earned it the nickname "aging pigment." AGE distribution in the canine brain resembles closely that observed in humans. A differentiating point, though, is the progression time: AGE formation proceeds faster in canines, a feature also shared by the process of diffuse plaque development.

	HISTOPATHOLOGICAL CHANGES OF THE NEURODEGENERATED CANINE BRAIN

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The histoanatomical alterations observed in neurodegenerated canine subjects parallels that of human counterparts. Changes affect the gross anatomy of the brain, meninges, choroid plexuses and the extended cerebral vasculature, meningeal and parenchymal vessels (27). An overall reduction in cerebral hemisphere volume, which is associated with gyral atrophy and widening of the sulci of the cerebral cortex, cortical atrophy (especially at the frontal and temporal lobes) and enlargement of the brain ventricles, with concomitant increase in the cerebrospinal fluid (CSF) volume, appear to be some inevitable alterations accompanying neurodegeneration. Nevertheless, some studies have suggested that the apparent decrease in volume might be a falsely alleged view, given that there have been volumetric studies that have failed to detect any correlation between declines in brain volume and advanced aged in canine subjects (28).

In contrast, magnetic resonance imaging experiments show that the cerebral vasculature suffers more from the extensive Aß deposition but does not seem to sustain any gross anatomical changes (29). Vascular volume appears to remain unaffected, although there is a perivascular space enlargement. Aß accumulation, which starts in the large cerebral vessels, particularly the tunica media of large arteries(30), is thought to be the primary mediator of a restricted but detectable breakdown of vessel integrity, mainly caused by degeneration of vessel wall smooth muscle cells (31). The vasculature also seems to maintain its overall anatomical properties despite hints of a tendency of increase in blood–brain-barrier (BBB) permeability with increasing age. It appears that there is a decline, although in functional performance as cerebral blood flow reduction and concomitant glucose and O₂ supply decline in brain tissue are unavoidable.

	ACKNOWLEDGMENTS

 
The authors thank Cheryl Cotman for providing the picture in Figure 1 and Drs. Chris and Paul Jones for their technical assistance.

	FOOTNOTES

 
¹ Presented as part of the Waltham International Symposium: Pet Nutrition Coming of Age held in Vancouver, Canada, August 6–7, 2001. This symposium and the publication of symposium proceedings were sponsored by the Waltham Centre for Pet Nutrition. Guest editors for this supplement were James G. Morris, University of California, Davis, Ivan H. Burger, consultant to Mars UK Limited, Carl L. Keen, University of California, Davis, and D’Ann Finley, University of California, Davis.

² Supported by grants from the University of Nottingham, Medical School, Nottingham, UK.

⁴ Abbreviations used: Aß, ß-amyloid peptide; AD, Alzheimer’s disease; APP, amyloid precursor protein; NFT, neurofibrillary tangles; Ub, ubiquitin.

	LITERATURE CITED

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