HIV associated dementia (HAD) is a major cause of potentially treatable cognitive decline. Despite decreased AIDS morbidity and mortality with highly active anti-retroviral therapy (HAART), the prevalence of HAD is increasing. Neuropathologic studies show that there is persistent inflammation in the brains of individuals with long-standing dementia even if they have been treated with HAART. Chronic inflammation contributes to CNS damage and the presence of activated microglia is a stronger correlate to dementia than the CNS HIV load. In long-term survivors with HAD, the pathological consequences of HIV induced neuroinflammation are compounded by the comorbidity of aging. Alzheimers disease (AD) is the most common cause of age related cognitive decline, and it shares neuropathologic features with HAD. These findings suggest that there may be common disease mechanisms in HAD and AD.
Microglia, the CNS resident immune cells, are activated in both AD and HAD and they are primarily responsible for the CNS inflammation seen in both disorders. When microglia are activated, they release inflammatory cytokines and neurotoxic substances. Microglia activation occurs in vitro in response to HIV infection and to exposure to the soluble HIV glycoprotein gp120. The presenilins (PS), PS1 and PS2, were originally identified as two of the three causative genes in familial AD. PS are the catalytic component of the gama-secretase complex that cleaves amyloid precursor protein (APP) to produce the amyloid-beta peptide found in Alzheimers plaques. PS can cleave substrates other than APP including Notch, ErbB4, and the p75NTR neurotrophin receptor, which mediate signaling in developmental, inflammatory and growth factor pathways. PS interface directly with inflammatory pathways and PS2 can be upregulated by inflammatory cytokines. PS1 and PS2 can also modulate signaling pathways independent of its function as a gama-secretase. We have shown that PS2 protein is increased in microglial cells of HAD patients by histopathology. Furthermore, we find that microglia activated by gp120 demonstrate elevated PS2 protein.
Society for Neuroscience 2005 poster presentation
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