Natural models

Aged animals, in particular aged rats, dogs, and nonhuman primates, can also be used as natural models of age-related cognitive decline. Each differs in its lifespan, so the term 'aged' is relative. For rats, adults are designated in the range of 5-6 months and aged animals are typically 20-26 months. In cognitive tests, e.g., delayed match-to-sample or Morris water maze, aged rats perform worse than their adults. However, no amyloid or neurofibrillary pathology is evident in aged rats; thus, the cognitive decline is attributed to age-related cholinergic hypofunctionality. The aged canine (7-14 years) has gained face validity as a model of human aging and dementia, i.e., AD, as dogs accumulate Ab neuropathology in their brain and exhibit impairments in learning and memory with progressing age.23 Like humans, the more toxic and less soluble peptide Ab42 accumulates prior to deposition of Ap40 in dogs and, importantly, the amyloid sequence is identical. Based upon performance in visuospatial and object recognition memory tasks, dogs can be classified as successful agers, impaired or severely impaired, paralleling the human classifications of successful aging, MCI, and dementia. Nonhuman aged (> 20 years) primates (rhesus, macaque, and cynomolgus monkeys) that more closely model human cognition can be used to assess task impairment and reversal by NCEs. Like the dog, aged monkeys show a propensity to accumulate Ap42 and develop senile plaques,24 thus representing a model with greater face validity to AD than the rat.

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