Natural Models Of Alzheimerlike Pathology

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Several animal species naturally develop senile plaques, cerebral amyloid angiopathy (CAA), and (to a limited degree) tauopathy with age. The most comprehensively studied nonhuman animals have been primates and canines. These animals are well-suited for modeling AD neuropathology for the following reasons: (1) They have the human-like A^ sequence and develop senile plaques and CAA with age; (2) tau abnormalities (but not fully developed tangles) occur naturally with age in some primates and dogs; (3) the behavioral complexity of monkeys and dogs enables in-depth analysis of cognitive, social and motoric components of neurodegeneration; (4) both groups manifest age-associated decline of certain behavioral capacities; and (5) their large brains allow detailed in vivo imaging (Walker and Cork, 1999; Bussiere et al., 2002; Voytko and Tinkler, 2004).

Aging canine

Cerebral amyloid deposition was first noted in a nonhuman species in the 1950s by von Braunmuhl, who described senile plaques in elderly dogs. Since then, the characteristics of the deposits and the natural history of their emergence have been well established, as has their possible relationship to age-associated cognitive decline. In dogs, as in primates, the A^ peptide is identical in sequence to human A^. Normal rats and mice differ in three amino acids from humans. The deposits that arise in the parenchyma of the aged canine brain are usually diffuse in nature; i.e., fully developed, dense-cored senile plaques are relatively rare. However, cerebral amyloid angiopathy (CAA) is common in older dogs (Wegiel et al., 1995). CAA in canines, as in humans, primates, and transgenic mice, is associated with an increased incidence of intracerebral hemorrhage and possibly white matter lesions as well (Torp et al., 2000).

Af3 accumulation correlates with behavioral impairments in aged dogs (Colle et al., 2000), and with a regional loss of brain substance (particularly in the frontal lobes) beginning around 8 years of age (Tapp et al., 2004). As in all affected species, there is substantial variation in age-associated changes among animals of comparable age; in addition, controlled comparative studies of the development and composition of lesions in different breeds of dogs are lacking. The age-related cognitive decline in aged dogs can be ameliorated by a diet rich in antioxidants and mitochondrial co-factors, as well as by behavioral enrichment (Milgram et al., 2005; Siwak et al., 2005), and there is evidence that drugs used to treat cognitive decline in humans can be usefully tested in aged canines (Studzinski et al., 2005).

Aging primate

Information on the neurobiology of aging in nonhuman primates has grown steadily over the past four decades (Hof et al., 2002). By far the most thoroughly investigated species are the rhesus monkey (Macaca mulatta) and the squirrel monkey (Saimiri spp), although there is a burgeoning literature on other nonhuman primate species, including great apes, marmosets (Saguinus jacchus), cynomolgus monkeys (Macaca fascicularis), green monkeys (Chlorocebus aethiops), baboons (Papio hamadryas), and mouse lemurs (Microcebus murinus). We will focus here primarily on rhesus monkeys and squirrel monkeys as natural primate models of Alzheimer-like pathology.

Rhesus monkeys. Rhesus monkeys are Old World monkeys with a maximum life span of approximately 40 years; they reach puberty at 3-4 years of age, and females go through menopause at approximately 25 years of age (Walker, 1995). Age-related cognitive decline is well-documented in rhesus monkeys, but a dementia-like state has not been reported. Rhesus monkeys develop senile plaques with age, usually in their early-mid 20's (Walker and Cork, 1999). These lesions are cytologically and biochemically similar to human plaques, except that the abnormal neurites that surround the core are devoid of tau filaments. Indeed, although primates can manifest tau abnormalities in brain, fully formed neurofibrillary tangles have not yet been detected in any nonhuman primate, including the apes.

Squirrel monkeys. In addition to widely varying phenotypes and lifespans, nonhuman primates show species-specific patterns of age-associated lesion development in brain. Squirrel monkeys are small, New World primates with a maximum lifespan of approximately 30 years (Walker and Cork, 1999). They begin to form A^ deposits in the brain by the age of 13 years (around the age of menopause in females), and such lesions can be plentiful by 21 years. Unlike in rhesus monkeys, the A^-proteopathy in squirrel monkeys is predominantly in the walls of cerebral blood vessels. Senile plaques also are present in squirrel monkeys, but they are less common than is CAA. Infrequent neurons are immuno-reactive for hyperphosphorylated tau, but as in all nonhuman primates studied to date there are no fully developed neurofibrillary tangles.

Apolipoprotein E (ApoE) is heterogeneous in humans, and one form (ApoE4) is linked to an increased risk of AD and CAA. Intriguingly, all nonhuman primates are homozygous for apoE4; that is, their apoE resembles human apoE4 with arginines at positions 112 and 158. However, in nonhuman primates, threonine replaces arginine at position 61 of the human apoE sequence, which causes simian apoE to interact with lipoproteins similarly to human apoE3. Thus, neither ftAPP mutations nor apoE type account for the species-related variation in Aft-pathology, at least in nonhuman primates.

In summary, nonhuman primates and canines have been invaluable in illuminating the biochemistry, cytology and genetics of senile plaques, amyloid angiopathy and tau pathology in the aging brain, and they remain useful for testing emerging therapies for neuro-degenerative diseases (Studzinski et al., 2005; Walker et al., 2005). However, for a variety of reasons, a major component of which is their longevity, research with these species is limited in scope. The emergence of genetically engineered rodent models has greatly accelerated the investigation of AD-like pathogenesis in vivo.

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