Cerebral Malaria: Mechanisms of disease and neurological salvage

DESCRIPTION (provided by applicant): Greater than 20% of individuals with cerebral malaria (CM) suffer from persistent neurological and cognitive deficits long after successful anti-parasitic treatment. These deficits encompass a wide range of neuro-cognitive dysfunction. We have demonstrated in a murine model that CM results in a vasculopathy with increased levels of endothelin- 1 (ET-1), leading to a reduction of cerebral blood flow and a decrease in NAA/Cr ratio in the brains of mice on MRS [2]. Our preliminary data also demonstrate that just as with human disease, mice sustain cognitive dysfunction [42], which persists even after successful eradication of the parasite, as evidenced by significantly impaired performance in object recognition and spatial memory tests. Furthermore, CM mice had significant motor coordination deficits on the balance beam even after successful antiparasitic treatment. These cognitive and motor impairments were still evident on retesting 40 days after resolution of malarial infection. However, they were not accompanied by any significant degree of vascular damage, inflammation or astrogliosis. The lack of obvious pathology after parasitic cure suggests that these long-term neuro- cognitive deficits are the result of potentially reversible biochemical and physiological changes in brains of CM mice subsequent to the decreased blood flow and ischemia during the acute infection. We demonstrated that tau, a protein involved in neurofibrillary tangle formation in Alzheimer's disease, is aberrantly phosphorylated in cortical neurons of infected mice during CM. We believe that the aberrant tau phosphorylation is the end product of an altered signaling in the neurons of infected mice mediated by ET-1. We have found a down-regulation of the PI3K/Akt insulin signaling/ survival pathway in the brains of mice with CM. As a result of decreased Akt activation, the normal inhibition of GSK3 by Akt does not occur and tau becomes aberrantly phosphorylated. In addition, Akt is no longer able to facilitate the translocation of glucose transporters to the cell membranes and the cells are not able to uptake glucose. We propose that as a result of a reduction in cerebral blood flow, there is ischemia and neuronal damage associated with abnormalities in the insulin signaling/ survival pathway. This mechanism likely underlies the cognitive function impairment observed in CM and may yield therapeutic targets for adjunctive therapy in the management of CM.