Glial cells, with the extracellular matrix and blood vessels, comprise the microenvironment of the brain, and affect the plasticity of neural responses to aging and to disease. After entry into the brain of activated macrophages and the activation of microglial cells, the proliferation and activation of astrocytes (gliosis) occur [57
]. The extent of astrogliosis tends to be more widespread than the distribution of the activated microglia, facilitated by gap junctions [59
]. Gap junctions allow functional groupings of 10–100 astrocytes to communicate and exchange calcium signaling molecules, glucose, glutamate, and signals that propagate glial activation and apoptosis [60
]. Such astrocytic upregulation results in an increase in numerous protective factors, including neurotrophic and neuroprotective cytokines, cytokines that enhance survival and differentiation of the oligodendrocytes, chemokines that recruit blood-derived inflammatory cells, cell adhesion molecules that facilitate leukocyte entry through the blood–brain barrier, extracellular matrix molecules that affect the migration of astrocytes and oligodendrocytes, and antioxidants involved in the elimination of free radicals and protection against oxidative stress [59
]. As a result, the major role of the astrocyte in HAD may be in controlling inflammation and enabling a balance between tissue destruction and repair. With aging, this balance changes in several components.
Aging affects repair processes and induces a constant level of enhanced reactivity in both microglia and astrocytes. In older rats, signals from damaged cells are insufficient to activate further neuroprotection by astrogliosis, but are adequate for further activation of the microglia [63
]. Furthermore, activated microglia in older rats lose their ability to upregulate neurotrophic molecules such as insulin-like growth factor 1 [64
]. Insulin-like growth factor 1 is an important stimulator of proliferation and survival of neurons and oligodendrocytes [65
]. In older human brains, astrocytic activation in response to ischemic injury has been shown to occur more slowly, to be less pronounced, and to persist for a shorter duration compared with younger brains [66
]. Aging rats also demonstrate a reduced capacity for neuronal sprouting [64
]. Aging increases the microglial expression of proinflammatory cytokines, to include IL-1 in humans and IL-6 in mice, as well as the increased expression of CD4 cells and MHC-II within the white matter [67
]. Therefore, the aging brain may be more vulnerable to HAD by favoring inflammatory microglial responses over neuroprotective microglial responses, while limiting protection and repair by neurons and astroglia.
Both astrocytes and microglia from older animals proliferate readily in culture, but are less responsive than cells from younger animals to controlling factors such as granulocyte–macrophage colony-stimulating factor and transforming growth factor beta 1 [72
]. The loss of cytokine regulation of neural growth factors has been implicated in humans with HAD. IL-4 induces nerve growth factor secretion to enhance oligodendrocyte survival [73
]. IL-4 messenger RNA has been shown to be undetectable in the autopsied brains of patients with HAD, but is easily detected in the brains of most non-demented HIV-positive and HIV-negative individuals [74
Changes in the extracellular space can also affect glial and neuronal signaling. The loss of extracellular matrix macromolecules, the narrowing of the extracellular channels, and swelling of delicate astrocytic processes, with reduced non-synaptic astroglial uptake for glutamate, glycine, and -aminobutyric acid occur with aging [75
]. Excitatory neurotoxicity would be further enhanced by an increase in intracellular calcium and a reduction in calcium channel antagonist receptors, which have been demonstrated to occur in the brains of aging mice [76
]. Therefore, the aging brain may be at an increased risk of excitatory neurotoxicity. In HIV, excitatory neurotoxicity has been shown to be potentiated by gp120, Tat, and matrix metalloproteinases [77
Macromolecules and proteins (prealbumin, albumin, alpha 2-macroglobulin, IgG) permeate the blood–brain barrier more freely with aging [78
]. Choline and glucose permeability also changes with aging [80
]. The significance of these changes in HAD is uncertain. However, age-associated increases in blood–brain barrier permeability could affect the delivery into the cerebrospinal fluid of antiretroviral agents possessing significant protein binding.
In conclusion, preliminary data from the Hawaii Aging with HIV Cohort, as well as other available existing data, support a growing concern that increased rates of cognitive impairment may be present in older compared with younger HIV-seropositive individuals. A need clearly exists to define the impact of aging on the prevalence and incidence of dementia and to determine the distinctive risk factors that may be associated with such a decline in this unique aging sub-group of HIV-seropositive individuals.
Whereas immune function probably plays a pivotal role in the pathogenesis of neurocognitive dysfunction, other factors including co-morbid neurodegenerative disorders, vascular co-pathology, and astrocytic function may also contribute. By skewing the microenvironment of the brain to one that favors the harmful effects of microglial activation, and limiting compensatory and adaptive neuroglial responses, one might expect the aging brain to be at increased risk of injury in HIV and other disorders that induce sustained microglial activation.