Cerebral malaria (CM) is a severe and potentially fatal neurological manifestation of disease caused by infection with Plasmodium falciparum. Despite effective anti-malarial therapy, approximately 25% of CM survivors develop long-term neurological deficits, such as memory loss and motor coordination impediments. The mechanisms that mediate this neurocognitive impairment are not well understood. Neuronal injury has been associated with the neurological deficits in several neurodegenerative diseases and may contribute to the impairment seen in CM. In this regard, damage to neuronal axons has been observed in both human and murine experimental CM (ECM). Furthermore, improper regulation of tau protein, an axonal protein important for microtubule stability and cytoskeletal organization, has been demonstrated in mouse and human disease. The neuronal injury and neurocognitive impairment observed in CM may result, in part, from abnormalities in tau. We hypothesize that pathological tau is one of the main mediators of neuronal damage and subsequent neurocognitive decline in CM. To address this hypothesis, we propose the following specific aims:
AIM1 : To characterize the role of tau in ECM.
Aim1 a: To examine the localization and secretion of hyperphosphorylated tau in the brains of mice with ECM and compare our findings to mice with malaria-associated severe anemia and uninfected mice.
Aim1 b: To characterize the contribution of tau to the neuronal damage and the subsequent neurocognitive deficits which occur during ECM using both a monoclonal antibody against phosphorylated tau and tau-knock-out (KO) mouse experiments.
AIM2 : To determine the role of tau in an in vitro human CM model. We will challenge cultured immortalized human neurons with supernatants obtained from blood-brain barrier co-cultures of astrocytes and endothelial cells (with and without P. falciparum exposure) and determine the effects on neuronal morphology and function as well as tau protein. We will also quantify secreted and intracellular tau levels and examine whether targeting the protein immunotherapeutically with PHF-1 antibody reverses neuronal damage. Our goal for this project is to further establish tau as a significant contributor to the pathogenesis of CM. Targeting this protein therapeutically may prevent both damage to neurons as well as the subsequent neurocognitive impairment which occurs during disease.
Malaria results from Plasmodium infection and is one of the most prevalent diseases in the world today, affecting, among other regions, large portions of Africa and Southeast Asia. Cerebral malaria (CM) is a neurological manifestation of malarial disease and is widely considered the most aggressive outcome of infection. The pathogenesis of CM remains largely unknown;this proposal will characterize some of the mechanisms that contribute to this neurological syndrome with the goal of identifying factors that merit therapeuti consideration.
