Linking Cerebral Malaria Pathogenesis to APOE-Mediated Amyloidosis: Observations and Hypothesis

Abstract

Although most children with cerebral malaria fully recover, more than a fifth of the survivors develop post-discharge neurodevelopmental sequelae suggestive of advanced neuronal injury. However, the cerebral molecular processes initiating neurological dysfunction in cerebral malaria are still debatable. In this article, we explore available data and hypothesise that cerebral malaria might be linked to APOE-mediated amyloidosis, one of the pathological processes associated with Alzheimer's disease. If our hypothesis is tested and found to be true, it could have far-reaching implications for what we know about cerebral malaria pathogenesis.

Keywords: Plasmodium falciparum; Alzheimer’s disease; Amyloid-beta; Amyloidosis; Apolipoprotein E; Cerebral malaria.

Fig. 1

The cerebral spinal fluid (CSF) levels of amyloid-associated proteins are co-increased in cerebral malaria. A Volcano plot showing that the CSF protein levels of apolipoprotein E (APOE) and amyloid precursor protein (APP) are elevated in cerebral malaria (CM) compared to acute bacterial meningitis (ABM) at log₂Fold-Change > 2 and false discovery rate (FDR)-adjusted p-value < 0.05. Spectrum searches were performed using Maxquant version 2.0.3, and moderated t.test in limma R package was used to perform the statistical analysis. The colours depict the following: blue, proteins downregulated in CM; grey, not significantly altered proteins; and red, proteins upregulated in CM. Consistent with what was observed previously [33], lipocalin 2 (LCN2), myeloperoxidase (MPO) and lactotransferrin (LTF) have lower CSF protein levels in CM compared to ABM. B Boxplots comparing the CSF protein abundance of APOE and APP between CM (n = 22) and ABM (n = 33). The centre lines show the medians; limits show the median ± interquartile range; whiskers show values 1.5 times above or below the 75th and 25th percentiles, respectively; and each point represents a sample. C Scatterplot showing that CSF protein levels of APOE (x-axis) and APP (y-axis) were significantly positively correlated in CM but not in ABM. The Spearman’s rank correlation test was used to calculate the correlation statistics. D Enrichment analysis [34] showing the top four disease ontology terms associated with CM compared to ABM. Colour depicts − log10 (p-value) while numbers show the enrichment score. E Overlap of proteins enriched in CM and ABM [33] with AD-altered proteins from a previous meta-analysis study [35]

Fig. 2

The APOE-APP hypothesis of cerebral malaria. Parasite sequestration in the brain capillaries can trigger the upregulation of APOE and APP, accumulation of amyloid-beta peptides and phosphorylation of neuronal tau. The APOE4 isoform can cause alteration of the blood–brain barrier (BBB) and neuroinflammation. Similarly, brain hypoperfusion may trigger dysregulated vasodilation and breakage of BBB, leading to leakage of vascular material into the brain parenchyma, resulting in further neuroinflammation and dysfunction of neurons. Therapeutic targets that block APOE or prevent the build-up of beta-amyloid peptides and phosphorylated tau could be explored as interventions for post-developmental sequelae observed in cerebral malaria survivors