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HIV-associated neurocognitive disorders (HAND) is an age-related comorbidity of individuals living with Human Immunodeficiency Virus (HIV) (Cheney et al. 2020). Patients with HAND experience behavioral and neurocognitive dysfunction caused by an overcompensatory inflammatory response by microglia and other macrophages in the wake of HIV infection. (Kempuraj et al. 2017). Unregulated neuroinflammation is triggered by the production of pro-inflammatory cytokines and chemokines from microglia in the presence of cellular debris and protein aggregation produced by dying cells having suffered central nervous system (CNS) insult. Neuroinflammation can modulate the function of cytoskeletal proteins and regulatory mechanisms like phagocytosis, but the mechanisms of impairment of these systems have yet to be clearly defined (DiSabato et al. 2016). Our study examines the impact of induced neuroinflammation on the regulatory cytoskeletal proteins, phospho-cofilin (p-cofilin) and cofilin, and their regulators, protein phosphatase slingshot homolog 1 (SSH) and lim domain kinase 1 (LIMK1). We modeled neuroinflammation in vitro through the treatment of BV2 cells with HIV-1 Tat protein, a suspected neuroinflammatory mediator, which can disable the phagocytic functions of microglia (Streit et al. 2004). Phagocytic intervention requires actin polymerization and depolymerization, which is controlled by cytoskeletal proteins like cofilin (Lauterborn & Gall 2017). Without CNS insult, cofilin exists in its phosphorylated, inactive form. SSH reactivates cofilin through dephosphorylation by phosphatases like SSH (Alhadidi & Shah 2017). If HIV-1 Tat is a true neuroinflammatory mediator, we anticipate that modulation of p-cofilin and SSH will be negatively correlated. Understanding the mechanisms through which neuroinflammation alters regulatory processes like phagocytosis and the cytoskeletal network is crucial to further understanding the pathology of neuroinflammatory diseases, including HAND, Alzheimer’s disease (AD), and Multiple Sclerosis (MS).
Derosa, Melanie and Varghese, Mekha, "Modulation of Cytoskeletal Protein Expression by Neuroinflammatory Mediators in Microglia" (2021). Biology Presentations. 39.
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