Effects of anti-tau immunotherapy on reactive microgliosis, cerebral endotheliopathy, and cognitive function in an experimental model of cerebral malaria

• Published in: Journal of neurochemistry Vol. 167; no. 3; pp. 441 - 460
• Main Authors: Akide Ndunge, Oscar B, Shikani, Henry J, Dai, Minxian, Freeman, Brandi D, Desruisseaux, Mahalia S
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2023
• Subjects: Animals; Brain - pathology; Cell activation; Cell injury; Cognition; Cognitive ability; Complications; Congestion; Disease Models, Animal; Encephalopathy; Extracellular matrix; Glial cells; Humans; Immunotherapy; Impairment; Infections; Inflammation; Injury prevention; Malaria; Malaria, Cerebral - complications; Malaria, Cerebral - therapy; Mice; Mice, Inbred C57BL; Microvasculature; Monoclonal antibodies; Neurodegenerative diseases; Neurodegenerative Diseases - pathology; Neuroinflammatory Diseases; Neurological diseases; Pathogenesis; Phosphorylation; Plasmodium berghei; Proteins; Tau protein; tau Proteins; Vascular diseases; Vector-borne diseases; neural damage; Plasmodium berghei; cerebrovascular congestion; neuroinflammation; memory impairment; glial activation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15972

Cerebral malaria (CM), a potentially fatal encephalopathy caused primarily by infection with Plasmodium falciparum, results in long-term adverse neuro-psychiatric sequelae. Neural cell injury contributes to the neurological deficits observed in CM. Abnormal regulation of tau, an axonal protein pathologically associated with the formation of neurofibrillary lesions in neurodegenerative diseases, has been linked to inflammation and cerebral microvascular compromise and has been reported in human and experimental CM (ECM). Immunotherapy with a monoclonal antibody to pathological tau (PHF-1 mAB) in experimental models of neurodegenerative diseases has been reported to mitigate cognitive decline. We investigated whether immunotherapy with PHF-1 mAB prevented cerebral endotheliopathy, neural cell injury, and neuroinflammation during ECM. Using C57BL/6 mice infected with either Plasmodium berghei ANKA (PbA), which causes ECM, Plasmodium berghei NK65 (PbN), which causes severe malaria, but not ECM, or uninfected mice (Un), we demonstrated that when compared to PbN infection or uninfected mice, PbA infection resulted in significant memory impairment at 6 days post-infection, in association with abnormal tau phosphorylation at Ser /Thr (pSer /Thr ) and Ser (pSer ) in mouse brains. ECM also resulted in significantly higher expression of inflammatory markers, in microvascular congestion, and glial cell activation. Treatment with PHF-1 mAB prevented PbA-induced cognitive impairment and was associated with significantly less vascular congestion, neuroinflammation, and neural cell activation in mice with ECM. These findings suggest that abnormal regulation of tau protein contributes to cerebral vasculopathy and is critical in the pathogenesis of neural cell injury during CM. Tau-targeted therapies may ameliorate the neural cell damage and subsequent neurocognitive impairment that occur during disease.