Association of early experience with neurodegeneration in aged primates
Introduction
Neuronal survival (Beaulieu and Colonnier, 1989), spine density (Comery et al., 1996), and the establishment of neuronal circuitry (Fox, 1992) are influenced by experience and environment during nervous system development. Experience can also alter cortical dendrite complexity, synapse number and neural stem cell number in the adult brain (Kempermann et al., 1998, Kleim et al., 1996). Epidemiological studies suggest that environmental experience may also influence the risk of developing the most common neurodegenerative disorder, Alzheimer's disease (Snowdon, 2003, Stern et al., 1994). For example, early life factors including education and “creative indices” have been associated with an increased prevalence of Alzheimer's disease (Snowdon et al., 1996).
The study of non-human primates may shed light on mechanisms underlying neuronal vulnerability associated with aging and disease. Aged rhesus monkeys develop cortical β-amyloid plaques that cross-react with antibodies against amyloid filaments and their constituent proteins derived from the brains of Alzheimer's disease subjects (Selkoe et al., 1987). The present study examined the potential influence of early environmental experience on the appearance of neurodegenerative alterations in late life in non-human primates. The brains of monkeys that had been reared under standard or atypically small housing conditions in early life were subsequently made available late in the animals’ lives to the authors of this study. We investigated and confirmed with reasonable confidence the distinct early life housing conditions of the monkeys, and then quantitatively examined β-amyloid plaque density and synaptophysin immunoreactivity in the brain. We find an association between early life experience and late life risk of exhibiting neurodegeneration.
Section snippets
Subjects
Adult and aged rhesus monkeys were subjects of this study. In late life, when the subjects became available to study investigators, all animals were housed at the California National Primate Research Center and animal care procedures adhered to AAALAC and institutional guidelines. Earlier in life, some subjects were raised in other primate facilities under different housing conditions, including “standard” housing conditions and “small” cages. Group 1 (n = 23 subjects; mean age 25.4 ± 4.3 years)
Results
Early environmental history was significantly associated with risk of amyloid plaque formation in the aged monkey cortex. Subjects raised in smaller cages exhibited a significant, 7.5-fold mean increase in both the density of β-amyloid plaques/mm2 and in amyloid plaque load in the superior temporal gyrus, compared to aged animals raised in standard-sized cages (Fig. 1; t-test, p < 0.001). Considerable individual variation was evident among aged subjects raised under small housing conditions, as
Discussion
To our knowledge, this is the first demonstration that structural features of the brain in the context of normal aging are influenced by early life experience. Monkeys reared in cages of small size exhibited a significantly increased density of amyloid plaques and a significant reduction in synaptophysin immunolabeling compared to aged monkeys raised under standard housing conditions. Synaptophysin is a protein associated with presynaptic vesicles, and its levels correlate with other synaptic
Acknowledgements
This work was supported by the NIH (AG10435) and the California Regional Primate Research Center Base Grant (RR00169), and the Shiley Family Foundation.
Disclosure statement: The authors have no conflicts of interest to declare.
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