Cerebral malaria: Mechanisms of vascular disease and neuronal damage

Abstract

Cerebral malaria (CM) is a potentially fatal neurological disease resulting from Plasmodium falciparum infection. Despite successful anti-malarial treatment, approximately 25% of CM survivors develop long-term neurocognitive deficits, including memory loss and motor coordination impediments. We observed a similar phenomenon in an experimental model involving infection of C57BL/6 mice with the CM-causing murine strain Plasmodium berghei -ANKA (PbA). Neuronal injury has been linked to neurocognitive impairment in neurodegenerative disease and may contribute to the deficits seen in CM. In this regard, damage to neuronal axons has been observed in both human and murine experimental CM (ECM). We hypothesized that the neuronal injury in CM results, in part, from altered signaling in the Akt/GSK3beta cell survival pathway and abnormalities in their downstream effector tau, an axonal protein important for microtubule stability and cytoskeletal organization. Improper regulation of tau induces a rise in its phosphorylated levels, which renders the protein incapable of interacting with microtubules to perform its functions. We observed Akt/GSK3beta signaling dysregulation in the brains of mice with neurological disease, and an increase in phosphorylated tau and axon insult in several regions of the central nervous system. Abnormal tau regulation has also been linked to hyper-inflammation, a common feature of CM. In malaria-infected mice, we observed an increase in mRNA expression of several pro-inflammatory cytokines as well as extensive congestion of vessels with infiltrating leukocytes and red blood cells. Interestingly, we found that memory loss was prevented in ECM mice, following treatment, in separate experiments, with both sodium orthovanadate, a phosphatase inhibitor which indirectly leads to Akt activation, as well as the mood stabilizer lithium, which has known actions on GSK3beta signaling. Lithium therapy also prevented ataxia in infected mice with cerebral symptoms. Administration of the immunotherapeutic PHF-1 antibody, which has been shown to regulate phospho-tau levels in murine models of Alzheimer's disease, resulted in a similar improvement in memory. In addition, treatment with either the antibody or the microtubule-stabilizing compound combretastatin A-4 appeared, preliminarily, to regulate neuroinflammation. Overall, our findings support the utility of targeting Akt/GSK3beta/tau signaling as a means to ameliorate the neuropathology and cognitive impairment that take place during CM.