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Parkinson's disease is characterized by bradykinesia, rigidity and a resting tremor and the underlying basis for those symptoms is the loss of dopaminergic cells in the nigrostriatal system. Similar to PD, an age-related decrease locomotor activity and the expression of tyrosine hydroxylase immunoreactivity has been observed in rhesus monkeys, but the reason for this decrease in dopaminergic function remains to be elucidated. Trophic factors such as glial cell line derived neurotrophic factor (GDNF) and neurturin sustain the dopaminergic phenotype in midbrain neurons and act through a common receptor tyrosine kinase (RET). Examination of RET expression by immunohistochemistry was performed on sections of tissue containing the substantia nigra pars compacta of young, middle, and old aged rhesus monkeys. Stereological estimates of the number and cellular area of RET-immunoreactive cells found no change with age. Estimation of changes in RET protein using fluorescence intensity measurement was also similar across age groups. The results indicate that the mechanisms of GDNF and neurturin signaling remain intact with age, and therefore these trophic factors may be able to enhance the dopaminergic function of neurons in the nigrostriatal system, when administered to individuals of any age.

Aging remains the strongest risk factor for developing Parkinson's disease (PD), and there is selective vulnerability in midbrain dopamine (DA) neuron degeneration in PD. By tracking normal aging-related changes with an emphasis on regional specificity, factors involved in selective vulnerability and resistance to degeneration can be studied. Towards this end, we sought to determine whether age-related changes in microglia and astrocytes in rhesus monkeys are region-specific, suggestive of involvement in regional differences in vulnerability to degeneration that may be relevant to PD pathogenesis. Gliosis in midbrain DA subregions was measured by estimating glia number using unbiased stereology, assessing fluorescence intensity for proteins upregulated during activation, and rating morphology. With normal aging, microglia exhibited increased staining intensity and a shift to more activated morphologies preferentially in the vulnerable substantia nigra-ventral tier (vtSN). Astrocytes did not exhibit age-related changes consistent with an involvement in regional vulnerability in any measure. Our results suggest advancing age is associated with chronic mild inflammation in the vtSN, which may render these DA neurons more vulnerable to degeneration.

In the present study, we examined the relationship between ApoE and amyloid containing profiles within the cerebral cortex of young, middle aged, and aged Rhesus monkeys. Polymerase chain reaction analysis revealed a pattern consistent with the ApoE e4 phenotype in the rhesus monkey similar to that reported in humans. We found numerous ApoE immunoreactive plaques within the temporal neocortex and amygdala, whereas the hippocampus contained only a few such plaques. Although virtually all ApoE-immunoreactive plaques coexpressed beta-amyloid, most plaques were beta A4 positive/ApoE immunonegative within the aged monkey cortex. Moreover, we observed a close correspondence between ApoE and thioflavin-positive (i.e., amyloid) plaques suggesting that ApoE may play a critical role in the conversion of beta A4 to its beta-pleated form. Because ApoE, beta A4 and amyloid are expressed in plaques within the aged Rhesus macaque cortex, this species may provide an in vivo model for investigations aimed at clarifying the interactions between these proteins in normal and pathologic aging.

Previous investigations have demonstrated an almost exclusive “coupling” between the receptor for nerve growth factor and cholinergic neurons within the basal forebrain. The present series of experiments were carried out to address two questions. First, what is the status of nerve growth factor receptor-containing neurons within the basal forebrain of patients with histopathologically confirmed diagnoses of Alzheimer's disease (AD)? More importantly, the second experiment assesses the degree to which the receptor for nerve growth factor and choline acetyltransferase remain colocalized within AD basal forebrain. A “decoupling” of this relationship, in which nerve growth factor receptors are no longer present upon magnocellular cholinergic neurons, would suggest that a loss of trophic support is functionally antecedent to the neuronal shrinkage and neuronal death seen in the basal forebrain in AD. Data obtained from six AD cases and four normal controls demonstrated an extensive reduction in number and shrinkage in size of nerve growth factor receptor containing neurons within the Ch4 region of the basal forebrain. Double label studies using either immunofluorescence or immunoperoxidase techniques demonstrated that the receptor for nerve growth factor and choline acetyltransferase remain colocalized in AD patients. This was true for neurons exhibiting either healthy or dystrophic morphological profiles. These data confirm previous studies, demonstrating that both a loss and shrinkage of cholinergic neurons occurs within the AD basal forebrain. The results of the present immunohistochemical investigation suggest that the degenerative changes associated with these neurons do not result from impaired trophic support related to a loss of NGF receptors. However, the presence of NGF receptors on remaining cholinergic basal forebrain neurons in AD patients suggests that these neurons would still be responsive to NGF administration.

The relative value of animals with memory impairments, due either to experimental lesions or aging processes, is dependent upon the specific hypothesis being tested. The experimental approaches described in the preceding reviews are valuable for basic studies on learning and memory in the mammalian brain. However, because of important differences between available model systems and human disease states, such as Alzheimer's disease, their use at present may be insufficient for understanding and developing treatment strategies for human cognitive dysfunctions. In this commentary, different aspects of animal models of memory dysfunction will be discussed relative to their ability to assess the structural and functional consequences of central nervous system (CNS) repair.

A role for impaired NGF mechanisms as an underlying component in the pathogenesis of Alzheimer's disease has yet to be realized. However, circumspect examination of the available data fails to provide sufficient evidence for rejecting this notion and further systematic evaluation along each step of NGF's mechanism of neurotrophic action is still required. This commentary argues that NGF may be involved in the degeneration observed in the basal forebrain in AD, or at the very least, plays a dynamic role in the disease process.