Neuropathology in non-human primates

Abstract

Non-human primates develop senile plaques that are similar to those observed in humans, in addition to experiencing age-related declines in cognitive ability which may be similar to the cognitive deficits observed in elderly humans with dementia In the last decade, information regarding the biochemical properties ofbeta-amyloid, the primary constituent of senile plaques, has become available at a brisk pace. In addition, numerous proteins have been recently identified in plaques, although the role of such proteins in the pathogenesis of plaques or Alzheimer's dfsease remains unknown. Investigation of these plaque-associated proteins may offer clues to the events responsible for the accumulation ofbeta-amyloid in the brain. One protein implicated in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases is ubiquitin. This protein is involved in the cytosolic, ATP-dependent degradation of abnormal and short-lived proteins in all eukaryotic cells examined thus far. Studies of humans with neurological disorders, such as Alzheimer's disease and Creutzfeldt-Jakob disease, have identified ubiquitinated neurites surrounding plaques. Although the mechanism responsible for the accumulation of ubiquitinated products within dystrophic neurites is currently unknown, it has been suggested that protein turnover in these neurons may be altered by neurotoxic beta-amyloid in the surrounding neuropil. Although numerous studies utilizing human brain tissue have demonstrated ubiquitin around plaques, very few studies in non-human primates have investigated the association ofubiquitin with plaques. To investigate ubiquitin in the brains of non-human primates, dual-label immunohistochemistry was performed on sections from 15 monkeys (age range: 4 to 32 years) using primary antibodies against beta-amyloid and ubiquitin along with fluorescent secondary antibodies. Ubiquitin was observed to be localized in the majority (range: 55.7 to 100%) of plaques in the five aged monkeys possessing these lesions. Ubiquitin immunoreactivity generally appeared as granular structures with either the same orientation as plaques or localized in the periphery. These structures appear similar to the ubiquitinated neurites reported around the plaques in patients with Alzheimer's disease and Creutzfeldt-Jakob disease. The five plaque-containing monkeys also possessed varying degrees of cerebrovascular amyloid, but only two monkeys possessed granular ubiquitin immunoreactivity in the surroun.ding neuropil adjacent to these vascular lesions. In addition, an apparent age-related accumulation of dot-like ubiquitinated material was observed in these 15 monkeys that was not associated with plaques. These results suggest that perturbations in ubiquitin-mediated protein turnover exist within some neurons of the aging monkey brain. Furthermore, similar mechanisms may be responsible for the neuronal degeneration and accumulation ofubiquitinated products within dystrophic neurites of both humans and monkeys. Another protein recently implicated in the pathogenesis of Alzheimer's disease is apolipoprotein E, a plasma protein which plays a central role in cholesterol and triglyceride metabolism throughout the body. In the nervous system, apolipoprotein Eis believed to participate in the mobilization and redistribution of lipids during development and in neurons undergoing repair or remodeling processes. A polymorphic gene on chromosome 19 codes for apolipoprotein E, and three alleles are associated with the production of three major isoforms of apolipoprotein E. Epidemiologic studies demonstrating that the frequency of the apolipoprotein E e4 allele is significantly increased in patients with Alzheimer's disease suggest that apolipoprotein E may be an important etiologic agent in the pathogenesis of Alzheimer's disease, and the localization of apolipoprotein E in the major neuropathological lesions of Alzheimer's disease further supports this hypothesis. Despite numerous studies undertaken in humans, few studies have investigated the localization of apolipoprotein E in the plaques in non-human primates. Therefore, to study apolipoproteinE in the brains of these 15 non-human primates, sections were processed for dual-label immunohistochemistry against apolipoprotein E and beta-amyloid. Also, some sections were immunostained for glial fibrillary acidic protein and beta-amyloid to investigate the orientation of astrocytes to the plaques in these monkeys. Other sections were immunostained for apolipoprotein E and glial fibrillary acidic protein to determine if astrocytes in these monkeys demonstrate apoE immunoreactivity, since astrocytes have been suggested to be the primary source of the apolipoprotein E found in the brain. Immunoreactivity for apolipoprotein E was associated with all plaques and cerebrovascular amyloid in the five aged monkeys possessing these lesions. Astrocytes immunoreactive for glial fibrillary acidic protein were generally observed in the neuropil surrounding plaques, but none of the astrocytes examined in these monkeys were immunoreactive for apolipoprotein E. These results support a role for apolipoprotein E in the development of plaques and cerebrovascular amyloid in the brains of nonhuman primates. Furthermore, the failure to demonstrate apolipoprotein E immunoreactivity in the astrocytes in these monkeys suggests that the apolipoprotein E may be principally derived from cells in the brain other than astrocytes, such as microglial cells which also known to express apolipoprotein E and have been localized within the core of plaques. In summary, this study has shown that both ubiquitin and apolipoprotein E are-important constituents of plaques, in agreement with previous studies in non-human primates. The roles ubiquitin and apolipoprotein E play in the development of plaques await elucidation, and nonhuman primates provide the opportunity to expand upon the current body of information regarding the mechanisms of these proteins in disease processes. The non-human primate is a valuable model for which to study neuropathological and cognitive changes because it is so closely related to humans, as opposed to rats and mice, and monkeys possess a broad behavioral repertoire which easily lends itself to investigation.