Mechanisms Controlling Non-Amyloidogenic Processing in NMDA-Associated Excitotoxicity
HIV-associated neurocognitive disorders (HAND) are a spectrum of disorders characterized by neurocognitive impairments such as memory loss. Previous scholarly works have observed altered amyloid processing and the presence of amyloid-beta plaques in the brains of HAND patients, which is a hallmark of neurodegenerative disorders such as Alzheimer’s disease.
Imbalance of secretases involved in amyloid processing has been implicated in exacerbating the neurotoxic insult in HAND. BACE1 is critical in the pathology of these disorders, as its cleavage of amyloid precursor protein (APP) produces amyloid- β (Aβ). Increased activation of the main APP-processing enzyme of the amyloidogenic pathway, BACE1, and decreased activation of a secretase involved in non-amyloidogenic processing, ADAM10, are hypothesized to contribute to the progression of HAND. The brains of HAND patients have also been found to have elevated BACE1 levels, along with the accumulation of Aβ plaques. Moreover, postmortem brains from both AD have been found to have decreased activity of the non-amyloidogenic pathway, in which APP is cleaved by the alpha-secretase ADAM10, releasing the neuroprotective molecule soluble APPα (sAPPα). ADAM10 is regulated by the deacetylase sirtuin 1 (SIRT1).
Scholarly works in the field, as well as in our lab, have elucidated that HIV-induced neurotoxicity is due to overactivity of the glutamatergic system, specifically, through induction of the NMDA-type glutamate receptor (Lesné et al., 2005; O’Donnell et al., 2006). Therefore, cells were treated with NMDA, an agonist of this receptor, in order to model HIV-induced excitotoxicity, and co-treated with ADAM10 and SIRT1 activators to elucidate the mechanisms of non-amyloidogenic processing.
We hypothesize that NMDA leads to a decrease in ADAM10 and SIRT1 and this leads to increased neurotoxicity. Activating and/or rescuing ADAM10 and SIRT1 will rescue cells from this neurotoxicity. Through immunoblotting and immunocytochemistry, we assessed the effects of ADAM10 and SIRT1 activators on protein levels (ADAM10, SIRT1, and β-actin) and on neurotoxicity. We found that acitretin appears to be neuroprotective, NMDA treatment appears to decrease SIRT1, and ADAM10 appears to be increased with SIRT1 and ADAM10 activation (relative to vehicle controls). However, further experimentation is required to validate these results.