Aged Primates Research Articles

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.

Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus

In the dentate gyrus of the hippocampus, new neurons are generated from neural stem/progenitor cells (NPCs) throughout life. As aging progresses, the rate of neurogenesis decreases exponentially, which might be responsible, in part, for age-dependent cognitive decline in animals and humans. However, few studies have analyzed the alterations in NPCs during aging, especially in primates. Here, we labeled NPCs by triple immunostaining for FABP7, Sox2, and GFAP and found that their numbers decreased in aged macaque monkeys (>20 years old), but not in aged mice. Importantly, we observed marked morphological alterations of the NPCs in only the aged monkeys. In the aged monkey hippocampus, the processes of the NPCs were short and ran horizontally rather than vertically. Despite these alterations, the proliferation rate of the NPCs in aged monkeys was similar to that in young monkeys. Thus, morphological alterations do not affect the proliferation rate of NPCs, but may be involved in the maintenance of NPCs in aged primates, including elderly humans.

Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical-neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer's disease (AD) but for many other disorders involving cognitive deficits. Collectively, our research provided first evidence of the following: aged primates can be used as 'models' for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.

Age-related cognitive deficits in rhesus monkeys mirror human deficits on an automated test battery

Aged non-human primates are a valuable model for gaining insight into mechanisms underlying neural decline with aging and during the course of neurodegenerative disorders. Behavioral studies are a valuable component of aged primate models, but are difficult to perform, time consuming, and often of uncertain relevance to human cognitive measures. We now report findings from an automated cognitive test battery in aged primates using equipment that is identical, and tasks that are similar, to those employed in human aging and Alzheimer's disease (AD) studies. Young (7.1+/-0.8 years) and aged (23.0+/-0.5 years) rhesus monkeys underwent testing on a modified version of the Cambridge Automated Neuropsychological Test Battery (CANTAB), examining cognitive performance on separate tasks that sample features of visuospatial learning, spatial working memory, discrimination learning, and skilled motor performance. We find selective cognitive impairments among aged subjects in visuospatial learning and spatial working memory, but not in delayed recall of previously learned discriminations. Aged monkeys also exhibit slower speed in skilled motor function. Thus, aged monkeys behaviorally characterized on a battery of automated tests reveal patterns of age-related cognitive impairment that mirror in quality and severity those of aged humans, and differ fundamentally from more severe patterns of deficits observed in AD.

Research Into Neuroprotection Must Continue … but With a Different Approach

Geoffrey A. Donnan MD, FRACP Stephen M. Davis MD, FRACP Section Editors: Neuroprotective agents disrupting the ischemic cascade and salvaging the ischemic penumbra are being explored as a potential therapeutic option for stroke. Although a number of agents are neuroprotective in animal studies, none of the human trials have been positive, with the exception of the SAINT I trial.1 Unfortunately, the follow-up SAINT II trial had a negative result,2 and a great deal of pessimism regarding the future of neuroprotection has been generated. However, before abandoning neuroprotection as a strategy, it is important to examine where research in neuroprotection has brought us and how we can better design future animal and clinical studies. The main reason for failure has been poor translation from animal studies to clinical trials. Clinical trials often had prolonged therapeutic windows, small sample sizes, and failed to achieve adequate plasma levels of study medications. These problems lead to the Stroke Therapy Academic Industry Roundtable (STAIR) recommendations,3,4 which have greatly improved …

Impaired regulation of body temperature, energy balance and IGF-1 levels during chronic cold exposure in an aged primate

Impaired regulation of body temperature, energy balance and IGF-1 levels during chronic cold exposure in an aged primate

Vieillissement et rythmes biologiques chez les primates

All living organisms exhibit rhythmic activities in a wide variety of endocrine and behavioural parameters. These biological rhythms are endogenously generated by a circadian clock, and they are entrained by cyclic variations of environmental factors called synchronizers. Aging is associated with changes in amplitude and temporal organization of many daily and seasonal rhythms. In humans, daily rhythms of sleep, thermoregulation and hormonal secretion are severely altered with aging. Except in humans, studies on primates are scarce. However, age-related effects on biological rhythms are relatively consistent among primate species studied to date, including humans. Therefore, non human primates are of valuable use for such investigations. Most studies have been performed on the Rhesus macaque (longevity 35-40 years) and on the gray mouse lemur (longevity 10-12 years). Like in humans, the rest-activity rhythm becomes fragmented in aged primates, and shows an increased activity during the resting period. Aging induces a decrease in amplitude of the body temperature rhythm and an increase in energy consumption. Various hormonal secretions exhibit a decrease with aging, but the rhythmic components of these declines have not always been depicted. Moreover, changes (amplitude or phase) in daily variations depended of the hormonal secretion tested. Taken together, these results suggest that the biological clock in the brain would be a primary target of aging. The main central clock is located in the suprachiasmatic nucleus of the hypothalamus whose endogenous oscillations are entrained by light. In this brain structure, cellular function and sensitivity to light show drastic changes with age in the mouse lemur. The precise knowledge of age-related alterations of biological rhythms in primates can have important consequences on the development of new treatments to maintain or restore biological rhythmicity in the elderly.

Dopaminergic Substantia Nigra Neurons Project Topographically Organized to the Subventricular Zone and Stimulate Precursor Cell Proliferation in Aged Primates

The subventricular zone of the adult primate brain contains neural stem cells that can produce new neurons. Endogenous neurogenesis might therefore be used to replace lost neurons in neurodegenerative diseases. This would require, however, a precise understanding of the molecular regulation of stem cell proliferation and differentiation in vivo. Several regulatory factors, including dopamine, have been identified in rodents, but none in primates. We have, therefore, studied the origin and function of the dopaminergic innervation of the subventricular zone in nonhuman primates. Tracing experiments in three macaques revealed a topographically organized projection from the substantia nigra pars compacta (SNpc), but not the adjacent retrorubral field, to the subventricular zone: the anteromedial SNpc projects to the anteroventral subventricular zone, the posterolateral SNpc to the posterodorsal subventricular zone. Double immunolabeling for tyrosine hydroxylase and BrdU (5-bromo-2'deoxyuridine) incorporated into the DNA of proliferating cells showed that dopaminergic fibers approach proliferating cells in the subventricular zone. We investigated the effect of this nigro-subventricular projection on cell proliferation in six aged macaques, because the rate of neurogenesis differs between young adult and aged primates and because neurodegenerative diseases mainly affect aged humans. Three macaques were treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to decrease dopaminergic innervation of the subventricular zone. A significant decrease in the number of PCNA+ (proliferating cell nuclear antigen-positive) proliferating cells (-44%) and PSA-NCAM(+) (polysialylated neural cell adhesion molecule-positive) neuroblasts (-59%) was found in the denervated regions of the subventricular zone, suggesting that an intact dopaminergic nigro-subventricular innervation is crucial for sustained neurogenesis in aged primates.

Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates

Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.

Overexpression of heat shock proteins in pallido-nigral axonal spheroids of nonhuman aged primates

The occurrence of spheroids has been described in the globus pallidus (GP) and substantia nigra pars reticulata (SNr) of aged rhesus monkeys. Opinions vary as to the origin of spheroids. Ultrastructural and immunohistochemical analysis suggested that spheroids originate from degenerating axons or astroglia. In the present study, we have investigated the GP and SNr of aged monkeys (Macaca fascicularis and Macaca mulatta). Although immunoreactive for microtubule-associated protein (MAP) 1A, tau, amyloid precursor protein, synaptophysin and phosphorylated neurofilament, spheroids were not immunoreactive for MAP1B and MAP2. We confirmed the axonal nature of pallido-nigral spheroids in aged rhesus monkeys. Pallido-nigral spheroids have been reported to overexpress stress proteins, such as ubiquitin, alphaB-crystallin, and heat shock protein (Hsp) 27. We further evaluated the expression of Hsps in pallido-nigral spheroids. As well as being intensely immunoreactive for ubiquitin, alphaB-crystallin, Hsp27, and Hsp70, spheroids were immunoreactive for Hsp32 (heme oxygenase-1), Hsp40, Hsp60, and Hsp90. On the basis of these findings, we speculate that Hsp32-immunoreactive spheroids might be expressed as an oxidative stress response. Induction of other Hsps might play a role in protection of axons from the aggregation of neurofilament, MAPs and other proteins, and failure to protect degenerating axons might result in their proteolysis by the ubiquitin-proteasome system.

Menopausal Increases in Pulsatile Gonadotropin-Releasing Hormone Release in a Nonhuman Primate (Macaca mulatta)

Reproductive function in all vertebrates is controlled by the circhoral release of the neuropeptide, GnRH, into the portal capillary system leading to the anterior pituitary. Despite its primary role in sexual maturation and the maintenance of adult reproductive function, changes in the concentrations and pattern of GnRH release have not yet been reported in any primate species during the menopausal transition and postmenopause. Such knowledge is essential for ascertaining both the mechanisms for, and consequences of, the menopausal process. Here we used a push-pull perfusion method to measure and compare the parameters of pulsatile GnRH release in adult rhesus monkeys at 8.4 +/- 1.5 yr (young adult females, early follicular phase, n = 6) and 28.8 +/- 0.3 yr (aged females, n = 4, of which two monkeys were in the menopausal transition, and two were postmenopausal). Our results demonstrate that: 1) GnRH release is pulsatile in both young and aged monkeys; 2) mean concentrations of GnRH increase during reproductive aging; and 3) GnRH pulse frequency does not differ between aged monkeys and young monkeys in the early follicular phase. We conclude that not only do GnRH neurons have the continued capacity to release GnRH in a pulsatile manner but also they can do so with enhanced GnRH levels in aged primates. To our knowledge, this is the first direct demonstration of elevated pulsatile GnRH concentrations in a primate species during reproductive senescence, a result that may have implications for menopausal symptoms.

Biological and social predictors of immune senescence in the aged primate

The transition to geriatric status occurs at around 20 years of age in monkeys after which there is typically a decline in immune responses. However, the loss in immune vigor may be quite dissociated from chronological age in some of these long-lived animals. The degree to which natural killer (NK) cell activity is sustained in aged monkeys has proven to be a valuable prognostic of ultimate health and longevity. Another useful biomarker of cellular aging in the monkey is interleukin-6 (IL-6) release. For example, when endothelial cell cultures were generated from cerebral blood vessels, those derived from aged donors produced significantly more IL-6 in response to IL-1, LPS, and hypoxia. Despite this evidence of intrinsic aging, we have found that immune responses in old animals are quite responsive to contemporaneous conditions, including changes in housing or the first onset of illness. Indeed, these changes, especially the pathological processes associated with disease, may promote many age-related immune alterations at the end of the life span.

Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.

Animal models that simulate various aspects of human brain aging are an essential step in the development of interventions to manage cognitive dysfunction in the elderly. Over the past several years we have been studying cognition and neuropathology in the aged-canine (dog). Like humans, canines naturally accumulate deposits of beta-amyloid (Abeta) in the brain with age. Further, canines and humans share the same Abeta sequence and also first show deposits of the longer Abeta1-42 species followed by the deposition of Abeta1-40. Aged canines like humans also show increased oxidative damage. As a function of age, canines show impaired learning and memory on tasks similar to those used in aged primates and humans. The extent of Abeta deposition correlates with the severity of cognitive dysfunction in canines. To test the hypothesis that a cascade of mechanisms centered on oxidative damage and Abeta results in cognitive dysfunction we have evaluated the cognitive effects of an antioxidant diet in aged canines. The diet resulted in a significant improvement in the ability of aged but not young animals to acquire progressively more difficult learning tasks (e.g. oddity discrimination learning). The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies.

Conservation of neuron number and size in entorhinal cortex layers II, III, and V/VI of aged primates.

Past dogma asserted that extensive loss of cortical neurons accompanies normal aging. However, recent stereologic studies in humans, monkeys, and rodents have found little evidence of age-related neuronal loss in several cortical regions, including the neocortex and hippocampus. Yet to date, a complete investigation of age-related neuronal loss or size change has not been undertaken in the entorhinal cortex, a retrohippocampal structure essential for learning and memory. The aged rhesus macaque monkey (Macaca mulatta), a species that develops beta-amyloid plaques and exhibits cognitive deficits with age, is considered the best commonly available model of aging in humans. In the present study, we examined changes in total neuron number and size in layers II, III, and V/VI of the intermediate division of the entorhinal cortex in aged vs. nonaged rhesus monkeys by using unbiased stereologic methods. Total neuron number was conserved in aged primates when compared with nonaged adults in entorhinal cortex layer II (aged = 56,500 +/- 12,100, nonaged adult = 48,500 +/- 10,900; P = 0.37), layer III (aged = 205, 600 +/- 50,700, nonaged adult = 187,600 +/- 60,300; P = 0.66), and layers V/VI (aged = 246,400 +/- 76,700, nonaged adult = 236,800 +/- 69,600; P = 0.87). In each of the layers examined, neuronal area and volume were also conserved with aging. This lack of morphologically evident neurodegeneration in primate entorhinal cortex with aging further supports the concept that fundamental differences exist between the processes of normal "healthy" aging and pathologic age-related neurodegenerative disorders such as Alzheimer's disease.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

The neurotoxicity of amyloid beta protein in aged primates

Amyloid beta protein deposition is a universal feature of Alzheimer's disease brain. To investigate the effects of amyloid beta protein in aged primates, intracerebral microinjections of solubilized amyloid beta (Aβ(1-40)) and control peptides were made into the frontal cortex of 7 primates under stereotactic guidance. Control injections consisted of vehicle alone, a 37 amino acid non toxic peptide (A37), scrambled peptide (CA4), and reverse peptide (Aβ (40-1)). Amyloid beta peptide produced dose-dependent cortical lesions that were significantly larger than those produced by vehicle or by isomolar control peptides (3.28 and 2.20 fold larger respectively) (p= < 0.005). In 5 aged primates, the cortex surrounding the amyloid beta lesions contained argy-rophilic, thioflavine S fluorescent, Alz 50 and ubiquitin im-munoreacttve neurons and perikarya. The number of Alz 50 immunoreacttve neurons surrounding the amyloid beta injections was significantly greater (mean 127 ± 39) than the number found surrounding reverse peptide injections (mean 20 ± 13) and other control peptides (mean 0.8 ± 0.3) (p < 0.05). Neuronal and neuritic alterations were not found adjacent to the amyloid beta peptide lesions in young monkeys and control injections produced insignificant Alz 50 neuronal positivity. These findings suggest that amyloid beta peptide is neurotoxic in primate brain and that the cytoskeletal response to amyloid beta protein is specific and age-related.

Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons

The aim of this study was to investigate the proteolytic processing of the amyloid precursor protein (APP) in polarized primary cultures of hippocampal neurons. We have used the Semliki Forest virus (SFV) vector to express human APP695 in hippocampal neurons, sympathetic ganglia, and glial cells. The latter two cells secrete little or no APP, whereas hippocampal neurons secrete two forms of APP695, which differ in sialic acid content and in their kinetic appearance in the culture medium. In addition, rat hippocampal neurons expressing human APP produced significant amounts of the 4 kDa peptide beta A4. After 3 hr of metabolic labeling, the relative amount of beta A4 peptide to total cellular APP was 5.3%. Fibroblasts expressing APP695 using the same SFV vector mainly produced a related 3 kDa p3 peptide, a nonamyloidogenic fragment. Remarkably, the hippocampal neurons also produced significant amounts of beta A4-containing C-terminal fragments (10-12 kDa) intracellularly. Radiosequencing showed that these fragments were created at a previously described beta-secretase cleavage site and at a cleavage site 12 residues from the N terminus of the beta A4 domain (Thr584 of APP695), which we named delta-cleavage. Based on the observation that mature hippocampal neurons produce two potentially amyloidogenic fragments and secrete substantial amounts of beta A4 when expressing human APP, our results strengthen the hypothesis that neurons play a central role in the process of beta A4 deposition in cases of Alzheimer's disease and in aged primates.

Optic Nerve Injury

In Response: We appreciate the interesting comments from Drs. Roth and Roizen. However, we would like to address some of the issues they raised. 1) They discuss the proposal that the blood supply to the optic nerve is governed by autoregulation similar to that in the rest of the brain. However, the autoregulatory response appears to be decreased in aged primates fed an atherosclerotic diet [1]. The implication for elderly humans with atherosclerosis could be a possible risk of ischemic optic neuropathy (AION). While autoregulatory mechanisms have been identified in the circulations of the retina and optic nerve of primates, the prelaminar tissue of the optic disk, which is the site of ischemic damage in AION, has not been independently studied well enough to rule out an absence or relative inadequacy of such mechanisms. 2) We agree with their assertion that prolonged accidental pressure on the eye is likely to result in retinal dysfunction as well as optic nerve damage. We did state that in these cases retinal edema would be revealed by fundoscopic examination [2]. 3) We disagree that AION is as rare as Drs. Roth and Roizen believe. A recent survey of two academic centers reported four cases over a 2-yr period in patients undergoing prolonged spinal surgery [3], with another similar case being reported in the neurosurgical literature [4]. There has been no systematic study of the incidence of AION in patients undergoing general anesthesia, and since the onset of the disease may initially go unnoticed by the patient, it is not unreasonable to assume that cases occur without being detected during the immediate postoperative period. We still advocate that, when there is a probability of significant intraoperative blood loss and/or hypotension, particularly in patients reluctant to receive blood transfusion, the possibility of visual loss should be discussed preoperatively. 4) With respect to the postoperative visit, especially with patients who have sustained intraoperative blood loss and hypotension, a simple question such as "Can you see all right?" should be sufficient to ascertain any major visual changes. If the patient indicates there is a problem, early consultation may help to exclude other correctable causes and to reassure the patient that his or her concerns are being addressed adequately, although there is no known effective treatment for postoperative AION. 5) Regarding the results of the multicenter trial of optic nerve decompression, 42% of the patients with untreated AION did exhibit moderate improvement but not complete resolution [5]. We still believe that anesthesiologists need to be aware of this unpredictable and devastating complication for which there is no treatment. E. Lynne Williams, MB,BS, FRCA William M. Hart, Jr., MD, PhD Rene Tempelhoff, MD Department of Anesthesiology Washington University School of Medicine St. Louis, MO 63110-1093

Optic Nerve Injury

In Response: We appreciate the interesting comments from Drs. Roth and Roizen. However, we would like to address some of the issues they raised. 1) They discuss the proposal that the blood supply to the optic nerve is governed by autoregulation similar to that in the rest of the brain. However, the autoregulatory response appears to be decreased in aged primates fed an atherosclerotic diet [1]. The implication for elderly humans with atherosclerosis could be a possible risk of ischemic optic neuropathy (AION). While autoregulatory mechanisms have been identified in the circulations of the retina and optic nerve of primates, the prelaminar tissue of the optic disk, which is the site of ischemic damage in AION, has not been independently studied well enough to rule out an absence or relative inadequacy of such mechanisms. 2) We agree with their assertion that prolonged accidental pressure on the eye is likely to result in retinal dysfunction as well as optic nerve damage. We did state that in these cases retinal edema would be revealed by fundoscopic examination [2]. 3) We disagree that AION is as rare as Drs. Roth and Roizen believe. A recent survey of two academic centers reported four cases over a 2-yr period in patients undergoing prolonged spinal surgery [3], with another similar case being reported in the neurosurgical literature [4]. There has been no systematic study of the incidence of AION in patients undergoing general anesthesia, and since the onset of the disease may initially go unnoticed by the patient, it is not unreasonable to assume that cases occur without being detected during the immediate postoperative period. We still advocate that, when there is a probability of significant intraoperative blood loss and/or hypotension, particularly in patients reluctant to receive blood transfusion, the possibility of visual loss should be discussed preoperatively. 4) With respect to the postoperative visit, especially with patients who have sustained intraoperative blood loss and hypotension, a simple question such as "Can you see all right?" should be sufficient to ascertain any major visual changes. If the patient indicates there is a problem, early consultation may help to exclude other correctable causes and to reassure the patient that his or her concerns are being addressed adequately, although there is no known effective treatment for postoperative AION. 5) Regarding the results of the multicenter trial of optic nerve decompression, 42% of the patients with untreated AION did exhibit moderate improvement but not complete resolution [5]. We still believe that anesthesiologists need to be aware of this unpredictable and devastating complication for which there is no treatment. E. Lynne Williams, MB,BS, FRCA William M. Hart, Jr., MD, PhD Rene Tempelhoff, MD Department of Anesthesiology Washington University School of Medicine St. Louis, MO 63110-1093

Adrenergic and serotonergic receptors in aged monkey neocortex.

Autoradiography was employed to compare the distribution and density of adrenergic (alpha 1, alpha 2, and beta) and serotonergic (5-HT1 and 5-HT2) receptors in the neocortex of young adult (3 to 10 years of age) and aged (> 20 years of age) rhesus monkeys. The age-related changes in the density of adrenergic and serotonergic sites were area and layer specific. A decrease in the density of alpha 1 receptors occurred only in the superficial layers of the somatosensory cortex, whereas the density of alpha 2 receptors declined in layer I of the prefrontal cortex and in most layers of the motor and somatosensory regions. The increase in beta receptors was largely confined to the deep layers of the motor and somatosensory areas. The density of 5-HT1 sites decreased in most layers of the somatosensory cortex, while 5-HT2 receptors declined in the deep layers of the motor cortex and middle strata of the visual cortex. Overall, adrenergic and serotonergic receptors were least affected in the prefrontal cortex and most compromised in the motor and somatosensory cortex of aged primates.