Different Aß43 deposition patterns in the brains of aged dogs, sea lions, and cats.

Cerebral amyloid ß (Aß) deposition is a pathological hallmark of Alzheimer's disease (AD). There are several molecular species of Aß, including Aß40, Aß42, and Aß43, and the pathological roles of Aß43 have attracted particular attention in recent years. Aß43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aß42 and Aß40. Aß40 and Aß42 deposition have been demonstrated in several animal species, while Aß43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aß pathologies. In the present study, the deposition patterns of Aß40, Aß42, and Aß43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aß42, Aß43, and Aß40. However, diffuse SPs and capillary CAA lesions were negative for Aß40. In sea lions, all SPs and most CAA lesions were positive for Aß42, Aß43, and Aß40, while capillary CAA lesions were negative for Aß40. In cats, Aß42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aß43, but negative for Aß40. Double-labelling immunohistochemistry revealed the co-localization of Aß42 and Aß43. These findings suggest that Aß43 and Aß42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aß pathology.

Multiple infarcts and hemorrhages in the central nervous system of a dog with cerebral amyloid angiopathy: a case report.

BACKGROUND: ß-amyloid (Aß) can accumulate in the brain of aged dogs, and within vessels walls, the disease is called cerebral amyloid angiopathy (CAA). In humans, Alzheimer's disease and CAA are strongly correlated with cerebrovascular disease. However, in dogs, this association has not been extensively studied yet. The present report highlights the pathological and clinical features of a concomitant cerebrovascular disease and amyloid precursor protein (APP) accumulation in the brain of a dog. CASE PRESENTATION: A female, 16-year-old, Standard Poodle with a one-year history of cognitive deficits presented with an acute onset of right-sided postural reaction deficit and circling, left-sided head tilt, positional nystagmus, and ataxia. Due to poor prognosis the dog was euthanized, and pathological examination of the brain revealed an acute lacunar infarction within the thalamus extending to rostral colliculus. Additional findings included subacute and chronic areas of ischemia throughout the brain and areas of hemorrhage within the medulla. Immunolabeling revealed APP deposition within intraparenchymal vessels of frontal, temporal and occipital cortex, hippocampus, diencephalon, mesencephalon and myelencephalon, besides meningeal vessels walls. Glial fibrillary acidic protein (GFAP) immunolabeling showed marked astrocytosis around the acute area of infarction and within chronic areas of ischemia. Histological examination of the brain along with immunohistochemistry results showed a concomitant APP, which is an Aß precursor, accumulation within the neuroparenchyma and vessels (CAA) with histological evidences of a cerebrovascular disease in an aged dog. CONCLUSIONS: This report shows that APP accumulation in the brain can occur concomitantly to a severe cerebrovascular disease in a dog. Further studies are necessary to elucidate if cerebrovascular disease is associated with Aß accumulation in the brain of dogs.

Histological and immunohistochemical characteristics of cerebral amyloid angiopathy in elderly dogs.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the wall of cerebral blood vessels. The deposits of amyloid occur frequently in the blood vessels of the frontal, parietal and occipital cortex. OBJECTIVE: To examine the characteristics of CAA classified according to the Vonsattel scale in elderly dogs histologically and immunohistochemically as well as the semi-quantitative evaluation of the amyloid deposits in the different segments of the brain. ANIMALS AND METHODS: The brains of 36 dogs of different breeds and sexes, which had been routinely necropsied, were used and divided into two groups: dogs from 1 to 5 and 10 to 18 years old. The tissue sections were stained by hematoxylin-eosin, Congo red and immunohistochemically. RESULTS: Amyloid was accumulated in the wall of cerebral blood vessels in 70% of dogs over the age of 10 years predominantly in the frontal cortex. CAA was demonstrated in elderly dogs as follows: in the frontal cortex (n = 19 or 63%), the parietal cortex (n = 12 or 40%), the hippocampus (40%) and the cerebellum (n = 5 or 17%). The deposits of amyloid in the wall of blood vessels detected by Congo red staining were also Aß1-14 and Aß1-42 immunohistochemically positive. Most commonly, the amyloid deposits affected a moderate number of blood vessels. The accumulation of amyloid was immunohistochemically revealed in the blood vessel walls as well as in the senile plaques and neurons. CONCLUSION: The amount of amyloid in the arterial walls increased with age in dogs, whereas the amyloid accumulated in plaques was Congo red negative.

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases.

According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases.

Senile plaques and cerebral amyloid angiopathy in an aged California sea lion (Zalophus californianus).

Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) consisting of ß-amyloid (Aß) are major features in the brain of Alzheimer's disease (AD) patients and elderly humans and animals. In this study, we report the finding of SPs and CAA in an aged sea lion (30 years), which is the first demonstration of AD-related pathological changes in a marine animal. Histologically, SPs were observed at the cerebral cortex, most frequently at the frontal lobe, with two morphologically different types: the small round type and the large granular type. Only the small round SPs were positive for Congo red staining. The SPs were equally immunoreactive to Aß40 and Aß42 and were mainly composed of Aß with an N-terminal pyroglutamate residue at position 3. Amyloid depositions at vessel walls were noted at the meninges and within the parenchyma. Interestingly, double immunofluorescence staining for Aß40 and Aß42 showed that the two subtypes were deposited segmentally in different parts of the vessel walls. The lesions observed in the sea lion suggest that Aß deposition is widely present in various animal species, including marine mammals; however, the peculiar deposits similar to cotton wool plaques and the specific pattern of CAA are characteristic features of this animal.

Histopathological studies of senile plaques and cerebral amyloidosis in cynomolgus monkeys.

Senile plaques (SPs) and cerebral amyloid angiopathy (CAA), pathological hallmarks of Alzheimer's disease, have not been thoroughly investigated histopathologically in nonhuman primates. To determine the onset age and histopathological characteristics of SPs and CAA, we examined the brains of 64 cynomolgus monkeys (Macaca fascicularis) from 2 to 35 years old. Mature (classical and primitive) plaques appeared in 16 out of 25 monkeys that were >20 years old. Moreover, mature plaques were observed more frequently than diffuse plaques and were located in the temporal cortex of the superior or inferior gyri and amygdala. Diffuse plaques in contrast to mature plaques did not show definite tendencies in onset age and distribution. CAA appeared in more than 22-year-old monkeys in 10 out of 16 animals and was frequently observed in capillaries and often found adjoining mature plaques. During immunohistochemical examination, an antiserum for amyloid beta protein (A beta) 1-40 could detect all SPs, whereas a monoclonal antibody for A beta 8-17 could not detect any diffuse plaques and only one third of the primitive plaques. As for CAA, the polyclonal antiserum was more sensitive than the monoclonal antibody. The present study describes the histopathological features of SPs and CAA in old cynomolgus monkeys.

A retrospective study of canine senile plaques and cerebral amyloid angiopathy.

Epidemiologic and morphologic features of canine senile plaques (SPs) and cerebral amyloid angiopathy (CAA) were examined in 69 necropsied dogs. Dogs having only SPs (diffuse plaques) frequently suffered from malignant neoplasms, and their mean age was significantly lower than that of dogs with CAA only. Morphologically, diffuse plaques showed wide distribution compared with amyloid plaques or CAA and were predominantly concentrated in the frontal cortex. We were unable to find any significant relationship between the severity of the SPs and individual age. These findings may indicate that the occurrence of canine SPs is not strictly associated with aging only and that additional factors are related to the occurrence of SPs, especially diffuse plaques.

The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys.

Autopsy surveillance of 186 rhesus monkeys aged 20 to 36 years revealed that development of major geriatric diseases such as emphysema, coronary sclerosis, and cancer increased rapidly after the age of 25 years, and nearly 70% of the monkeys in each cohort group died by 30 years. According to our 12-year longitudinal survey, the age of biosenescence in captive rhesus monkeys begins around 25 years and the maximum longevity is 36 years. The incidence of cerebral beta-amyloidosis associated with plaque formation and cerebral angiopathy was observed in 51 brains of rhesus monkeys aged 25 to 36 years. Lesions were found in 31 of 51 aged brains (60%) and 6 monkeys over 34 years of age were all severely affected. Despite the size of the plaque, nearly all of them showed immunopositive beta-amyloid. Cerebral angiopathy coexisted in 10 of 31 plaque-positive brains. The basal prefrontal gyrus was the most common site and contained the highest density of plaques, followed by the amygdala region. The amyloid in the liver, spleen, adrenal and pancreatic islets in visceral amyloidosis showed no positivity to the beta-amyloid demonstrated in the brain. As in aged human brains, the incidence of age-dependent cerebral beta-amyloidosis in captive rhesus monkeys showed great individual variation.

Double-labeling immunohistochemical studies on canine senile plaques and cerebral amyloid angiopathy.

The relationship of senile plaques to neuronal cells, neurites, glial cells, or capillaries was examined using double labeling-immunostaining methods on the Bouin's solution-fixed serial brain sections from dogs. Compact deposits of beta protein (amyloid plaques) in the cerebral cortex always contained microvessels labeled by anti-collagen type IV antibody and some of them might be formed as the result of fusion of several perivascular beta amyloid deposits. In the periphery of those plaques swollen neurites recognized with anti-neurofilament antibody were sometimes present, but the relation between such plaques and neuronal cells or glial cells were unclear. Diffuse deposition of beta protein (diffuse plaques) was frequently developed beside neuronal cells, while most plaques did not contain glial cells. Some of those plaques were closely contact with microvessels, but some had no relation. Intact or irregularly arranged neurites were present in diffuse plaques. Such irregularity of the neurites were obvious in the plaques in the hippocampus as compared with those in the cerebral cortex. These results indicate the possibility that canine amyloid plaques would be formed as the result of amyloid degeneration of cortical capillaries, and diffuse parenchymal deposition of beta protein would originate from neuronal or neuritic processes.

Immunohistochemical analysis of constituents of senile plaques and cerebro-vascular amyloid in aged dogs.

Immunohistochemical analysis of constituents of senile plaques and cerebro-vascular amyloid in the brain of aged dogs was performed using antisera against beta protein, cystatin C, ubiquitin, tau, and neurofilament (NF). All types of senile plaques and cerebro-vascular amyloid in aged dogs were labeled by anti-beta protein serum. Cystatin C immunoreactivity was detected in neuronal cell bodies, primitive or classical plaques, and amyloid deposited around cerebral capillaries, but not in diffuse plaques and amyloid deposited in the media tunica of cerebro-meningeal arterioles. Ubiquitin-positive granules distributed widely in both gray and white matter of aged dogs, while they were very small in number in young dogs. Swollen neurites-like materials in primitive plaques or classical plaques were immunoreactive for anti-ubiquitin serum. Tau immunostaining labeled commonly axons and several neuronal or glial cells after hydrate autoclave pretreatment. Tau-positive components were observed very rarely in the corona of classical plaques. Most of swollen neurites-like structures of primitive or classical plaques were not reactive for anti-NF serum, and only a few plaques contained small numbers of NF-positive elements.

Immunohistochemical studies on canine cerebral amyloid angiopathy and senile plaques.

Amyloid protein was isolated from the cerebral meninges of 4 aged dogs with cerebral amyloid angiopathy. By immunoblot analysis, antiserum against synthetic oligo-peptide consisting of 1-28 amino acid of amyloid beta protein recognized prominent wide band ranging from 14 to 18 kilodalton (kd). When amyloid samples were solubilized by formic acid, the antiserum recognized lower molecular weight band ranging from 3 to 4 kd. Immunohistochemical studies on cerebral amyloid angiopathy and senile plaques were performed in 17 aged dogs. Anti-amyloid beta protein serum labeled amyloid deposits in cerebral vessel walls and senile plaques. Compact deposits of beta protein were detected in primitive or classical plaques. After using formic acid pretreatment, diffuse deposits of beta protein in the neuropil representing diffuse plaques were detectable. Classical and primitive plaques reacted with antiserum against glial fibrillary acidic protein, while not with antisera against alpha 1-antichymotrypsin, IgG and IgM. Amyloid deposits in the intestines of aged dogs examined, did not react with anti-amyloid beta protein serum.

Pathological studies on cerebral amyloid angiopathy, senile plaques and amyloid deposition in visceral organs in aged dogs.

The relationship between cerebral lesions such as amyloid angiopathy or senile plaques and amyloid deposition in the visceral organs were studied in 90 autopsy cases of dogs, 0 to 19-year-old. Cerebral amyloid angiopathy was detected in 28 aged dogs (mean age: 13.7-year-old) and was found mostly in or around the wall of cerebral meningeal arterioles and capillaries of the neocortex. That condition was often accompanied by cerebral hemorrhage in dogs more than 9 years of age. Senile plaques were detected in the neocortex of the brain of 12 dogs (mean age: 13.2-year-old) and classified into 3 subtypes, i.e., "diffuse plaque", "primitive plaque" and "classical plaque". Among those 3 subtypes of senile plaques, amyloid containing plaques were small in number. In the visceral organs of dogs with cerebral amyloid angiopathy, amyloid deposition was found in the vascular walls or connective tissues of small intestines at a high frequency and sometimes in the vascular walls of the heart, lung, liver and thyroid gland as well as in atrioventricular valves. Amyloid in both cerebral and visceral organs was congophilic and showed green birefringence under poralized light even after potassium permanganate oxidation.