Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease

Abstract

Microglia are associated with central nervous system (CNS) pathology of both Alzheimer's disease (AD) and the acquired immunodeficiency syndrome (AIDS). In AD, microglia, especially those associated with amyloid deposits, have a phenotype that is consistent with a state of activation, including immunoreactivity with antibodies to class II major histocompatibility antigens and to inflammatory cytokines (interleukin-1-beta and tumor necrosis factor-alpha). Evidence from other studies in rodents indicate that microglia can be activated by neuronal degeneration. These results suggest that microglial activation in AD may be secondary to neurodegeneration and that, once activated, microglia may participate in a local inflammatory cascade that promotes tissue damage and contributes to amyloid formation. In AIDS, microglia are the primary target of retroviral infection. Both ramified and ameboid microglia, in addition to multinucleated giant cells, are infected by the human immunodeficiency virus (HIV-1). The mechanism of microglial infection is not known since microglia lack CD4, the HIV-1 receptor. Microglia display high affinity receptors for immunoglobulins, which makes antibody-mediated viral uptake a possible mechanism of infection. In AIDS, the extent of active viral infection and cytokine production may be critically dependent upon other factors, such as the presence of coinfecting agents. In the latter circumstance, very severe CNS pathology may emerge, including necrotizing lesions. In other circumstances, HIV infection of microglia probably leads to CNS pathology by indirect mechanisms, including release of viral proteins (gp120) and toxic cytokines. Such a mechanism is the best hypothesis for the pathogenesis of vacuolar myelopathy in adults and the diffuse gliosis that characterizes pediatric AIDS, in which very little viral antigen can be detected.

Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

“…In PD brains, large numbers of human leukocyte antigen (HLA-DR)-positive reactive microglia were found in the substantia nigra (SN), a region in which the degeneration of dopaminergic neurons was most prominent (McGeer et al, 1988). In addition to AD and PD, results from both in vivo and in vitro studies have since established an association of microglial activation with the pathogenesis of human immunodeficiency virus (HIV) acquired immunodeficiency syndrome dementia complex, amyotrophic lateral sclerosis, multiple sclerosis, and prionrelated diseases (Dickson et al, 1993;Raine, 1994;Brown, 2001).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Furthermore, recent epidemiological studies indicate that the chronic use of nonsteroidal anti-inflammatory agents (NSAIDs) reduces the risk of PD and AD ( [39,152,154,225]) and inheritance of polymorphisms resulting in enhanced expression of various inflammatory mediators was reported to increase the risk of these two pathologies ( [32,246]). Importantly, activated microglia were found at the histopathological sites of several brain disorders, including neurodegenerative diseases such as AD, MS, PD, ALS (amyotrophic lateral sclerosis) and AIDS-associated dementia ( [56,93,116,153] and [192]). …”

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

“…A total of 84 genes related to the PCR array were analyzed in a 384-well format. The C T values were analyzed using an RT 2 Profiler PCR array data analysis template (SABiosciences). The samples were analyzed only if the test passed all the quality controls, including real-time efficiency and lack of DNA contamination.…”

“…Neuroinflammation is a common response to infection or injury of the central nervous system (CNS) and includes the induction of proinflammatory cytokines, the activation of glial cells, and the recruitment of inflammatory cells to the CNS. [1][2][3][4][5] Neuroinflammatory responses may depend on the initiation of innate immune responses triggered by the stimulation of intrinsic brain cells with pathogen-associated molecular patterns, the repeated structural motifs generated by microbes that are not normally found in the host, or by debris from apoptotic or necrotic cells after injury. The recognition of pathogen-associated molecular patterns is mediated by several families of germline-encoded receptors, called pattern recognition receptors.…”