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. 1999 Sep 14;96(19):10893-8.
doi: 10.1073/pnas.96.19.10893.

Age-associated Neuronal Atrophy Occurs in the Primate Brain and Is Reversible by Growth Factor Gene Therapy

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Free PMC article

Age-associated Neuronal Atrophy Occurs in the Primate Brain and Is Reversible by Growth Factor Gene Therapy

D E Smith et al. Proc Natl Acad Sci U S A. .
Free PMC article

Erratum in

  • Proc Natl Acad Sci U S A 1999 Dec 7;96(25):14668

Abstract

The effects of normal aging on the primate brain are incompletely understood. Although both human and nonhuman primates demonstrate clear functional declines in selective attention, "executive" functions, and some components of declarative memory with aging, most studies have failed to demonstrate extensive neuronal atrophy or loss as a substrate for these degenerative changes in primates. In particular, extensive age-related neuronal loss in memory-related brain regions such as the hippocampus and entorhinal cortex has not been found. However, it is possible that neuronal loss or atrophy might occur in subcortical nuclei that modulate the activity of neocortical regions, thereby accounting for altered cognitive function with aging. In the present study, we describe, to our knowledge for the first time, a significant and extensive decline in the number and size of immunolabeled neurons in subcortical cholinergic basal forebrain regions of aged rhesus monkeys, the best animal model of human aging, by using stereological methods. Notably, the loss of subcortical cholinergic neuronal markers in aged monkeys was nearly completely reversed by human nerve growth factor gene delivery. These findings (i) identify reversible cellular atrophy as a potential mechanism contributing to age-related cognitive decline in primates, (ii) suggest, when considered with other studies, that subcortical brain regions exhibit greater vulnerability to the effects of aging than cortical regions, and (iii) indicate that neurotrophin gene transfer may be an effective means of preventing neuronal atrophy or degeneration in age-related neurodegenerative disorders.

Figures

Figure 1
Figure 1
p75 immunolabeling in aged and nonaged monkeys. (a) Ch4i region in nonaged monkey exhibits normal distribution of cholinergic neurons. Ch4id: Ch4 nucleus, intermediate-dorsal component; Ch4iv: Ch4 nucleus, intermediate-ventral component. M, medial. Bar = 450 μm in a–d. (Inset) Normal p75-immunolabeled neurons and neurite density at 20-fold higher magnification. (b) Ch4i region in aged nongrafted monkey, showing fewer neurons that appear more pale than those of nonaged subjects. Inset indicates lower neuronal and neurite density than observed in nonaged monkey. (c) In contrast, p75-labeled neurons in monkeys with control grafts exhibit no evident morphological response to the adjacent graft. Neurons resemble those of nongrafted aged subjects in extent of loss of neuronal labeling and neurite density. (d) Ch4i region in aged NGF-grafted monkey shows restoration of neuronal and neuritic density. NGF-secreting fibroblast graft (G) is dark because of dense penetration by p75-labeled cholinergic axons. Many neuronal soma orient in the direction of the NGF-secreting cell source and extend axons into the graft. Inset demonstrates these changes at 20-fold higher magnification.
Figure 2
Figure 2
Neuronal quantification. Quantification of neuronal number (a) and size (b) in nonaged and aged monkeys. Aged monkeys exhibit a significant decline in the number (ANOVA P < 0.05) and size (P < 0.05) of p75-immunolabeled neurons compared with nonaged monkeys. Aged monkeys that have received grafts of control fibroblasts that express the reporter gene β-gal show losses in cellular markers identical to those observed in nongrafted subjects. In contrast, aged recipients of NGF-secreting cell grafts show significant amelioration of losses in immunolabeled cell numbers and size. Post hoc testing reveals significant losses only in the aged nongrafted and β-gal-grafted groups (∗).
Figure 3
Figure 3
Technique of double labeling for p75/ChAT. (a) A neuron in the cholinergic basal forebrain is single labeled for p75. (b) A different neuron in the same histological slice is single labeled for ChAT. (c) A third neuron in the same histological slice is double labeled for p75 and ChAT. Bar = 20 μm in a–c.
Figure 4
Figure 4
Cell grafts can be visualized and monitored in the living primate. (a) Grafts of NGF-expressing cells in bilateral basal forebrain cholinergic nuclei are visible on MRI as circular regions of attenuated signal (arrows). (b) The same slice after histological processing reveals healthy graft (G) tissue that is robustly penetrated by p75-labeled cholinergic axons. Bar = 450 μm.

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