Abstract
Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD). HIV promotion of an M1 antigen presenting cell (APC) - like microglial phenotype, through the promotion of CD40 activity, may impair endogenous mechanisms important for amyloid- beta (Aβ) protein clearance. Further, a chronic pro-inflammatory cycle is established in this manner. CD45 is a protein tyrosine phosphatase receptor which negatively regulates CD40L-CD40-induced microglial M1 activation; an effect leading to the promotion of an M2 phenotype better suited to phagocytose and clear Aβ. Moreover, this CD45 mediated activation state appears to dampen harmful cytokine production. As such, this property of microglial CD45 as a regulatory "off switch" for a CD40-promoted M1, APC-type microglia activation phenotype may represent a critical therapeutic target for the prevention and treatment of neurodegeneration, as well as microglial dysfunction, found in patients with HAD.
Highlights
Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD)
At least three phenotypic states of microglia exist based on developmental and pathophysiologic studies: (i) resting, ramified; (ii) activated nonphagocytic found in areas involved in central nervous system (CNS) inflammation; and (iii) reactive, phagocytic microglia observed in areas of trauma or infection [3,4,5,6,7] (Figure 1)
Macrophages and microglia are able to polarize into two major subtypes, categorized as M1 or M2 [8,9]
Summary
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