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.
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Introduction
Cerebral malaria (CM) is a neurological syndrome caused by Plasmodium falciparum, and its mechanism of pathogenesis is tightly linked to the adhesion and sequestration of parasitised erythrocytes in the brain microvasculature [1]. Vascular-related pathological events such as brain endothelial activation and dysfunction [2], infiltration of activated CD8+ T cells into the brain microvasculature [3] and disruption of the blood–brain barrier (BBB) [4] are thought to occur secondary to the sequestration of infected erythrocytes. However, since these pathological mechanisms are vascular-related, the exact molecular processes occurring in the brain tissues that cause neuronal dysfunction in CM are poorly understood. Although most CM patients fully recover, 15–20% die, and greater than 20% of the survivors develop long-term post-discharge neurodevelopmental sequelae, including hemiplegia, aphasia, cortical blindness and ataxia [5], indicating a similarity between CM and neurodegeneration. Here, we explore available literature and hypothesise that CM might share a common pathological pathway with Alzheimer’s disease (AD) despite the former being largely remediable.
APOE Modulates Amyloidosis in AD in a Gene Dose-Dependent Manner
AD is a neurological disorder caused by age-associated changes in the brain, alongside environmental and genetic factors. Some age-associated changes that could lead to AD include brain atrophy [6], vascular damage [7, 8], neuroinflammation [9], production of free radicals leading to excessive peroxidation of lipids [10] and dysregulation of energy metabolism in brain cells leading to energy deficits and neuronal dysfunction [11]. Some AD cases are caused by the accumulation and deposition of amyloid-β (Aβ) peptides in the brain, a process termed amyloidosis [12], followed by hyperphosphorylation of tau to form toxic neurofibrillary tangles, a process termed tauopathy [13]. However, some studies also report that tauopathy can occur independently of amyloidosis. The Aβ peptides are derived from the proteolysis of the neuronal amyloid precursor protein (APP) [12]. A cholesterol-transporting protein called apolipoprotein E (APOE), secreted primarily by astrocytes, plays a central role in AD by modulating either the transcription of APP [14] or the clearance of Aβ [15]. APOE and APP levels are increased in the cerebral spinal fluid (CSF) of AD patients [16,17,18] and in the brain tissues of transgenic mouse models of Aβ amyloidosis [19,20,21,22]. In addition, accumulating studies in mouse models of AD suggest that the absence of APOE, either genetically or pharmacologically, dramatically decreases Aβ amyloidosis in a gene dose-dependent manner [19,20,21,22,23,24]. APOE is expressed in three isoforms, APOE2, APOE3 and APOE4, at a single gene locus, with APOE4 being the leading genetic risk factor for AD [25] and the one associated with the highest levels of Aβ synthesis and deposition [14, 15]. Although the APOE4 variant is widely believed to contribute to neurodegeneration by promoting the accumulation of APP and Aβ [14, 15, 19,20,21,22,23,24], APOE4 has also been associated with vascular dysfunction and BBB leakage [7, 8].
Amyloidosis-Related CSF Proteins are Associated with CM
The role of APOE in CM pathogenesis has been considered [26,27,28]. An observational study reported that children (< 5 years of age) with APOE4 isoforms have a higher risk of developing and dying from CM compared to those with other isoforms [28]. Additionally, a recent study observed that APOE−/− mice did not develop experimental CM (ECM), even at 70–80% peripheral parasitemia, had lower parasite sequestration in the brain, reduced disruption of the BBB and decreased infiltration of T cells into the brain [27]. Another mouse study used immunochemistry to show that Aβ accumulates in the brain tissues of ECM-sensitive mice infected with P. berghei but not in ECM-resistant mice [29]. The APP protein was upregulated in the brain sections of patients who died from CM relative to those with no clinical cerebral pathology [30]. Also, increased CSF levels of tau were associated with long-term neurological and cognitive deficits in CM patients [31], and anti-tau immunotherapy prevented parasite-induced cognitive impairment and was associated with significantly reduced neuroinflammation and vascular congestion in ECM [32]. While primarily searching for biomarkers of acute bacterial meningitis (ABM) relative to CM, Njunge and colleagues used mass spectrometry to compare the CSF protein profiles of paediatric admissions with either of the two infections [33]. They observed that APOE was among the most upregulated CSF proteins in CM [33]. We reanalysed Njunge et al. proteomic data [33] and observed that in addition to APOE, the CSF levels of APP and other AD-related proteins such as NPTX1, PRNP, NCAM1, SPARC, AGT and IGF2 were also significantly elevated in CM compared to ABM (Fig. 1A, B; Supplementary File Table 1). We also noticed that APOE was significantly positively correlated to APP in CM (R = 0.5, p = 0.02) but not in ABM (R = 0.18, p = 0.32) (Fig. 1C), which was concordant with the gene dose-dependent amyloidogenic effect of APOE observed previously in AD [19,20,21,22,23,24]. When we performed disease ontology enrichment analysis [34], we found that genes upregulated in CM were strongly associated with AD-related terms such as “amyloidosis”, “Alzheimer’s disease” and “tauopathies” (Fig. 1D). Next, we obtained a list of 162 CSF proteins reported in at least two studies to be significantly altered in AD patients compared to healthy controls [35] and overlapped them with proteins that we found significantly enriched in CSF from CM patients compared to ABM (Supplementary File Table 2). This analysis showed that 68 of the 168 AD-altered CSF proteins, including APOE and APP, overlapped with those enriched in CM compared to ABM, while only 12 overlapped with those enriched in ABM (Fig. 1E, Supplementary File Table 2). These observations and data suggest that AD-linked proteins are strongly associated with CM.
Concluding Remarks
We have hypothesised and provided partial evidence that druggable AD signatures are augmented in CM. This information might benefit the search for treatment and management of both AD and CM. For instance, amyloidosis-targeted and anti-APOE therapies could be explored to prevent post-infection neurodevelopmental sequelae observed in some children after CM recovery [5] (Fig. 2). Furthermore, the general reversibility of CM might provide insights into how to reverse or prevent the progression of AD. However, additional scientific data will be required to support the amyloidosis hypothesis of CM pathogenesis. First, a multicentre large CSF proteomic study would be required to confirm the co-upregulation of APOE and APP in CM patients relative to age-matched patients with non-plasmodial encephalopathies and healthy community controls. In addition to proteomics, we propose an integrated analysis of the CSF transcriptomes, including mRNA, lncRNA and miRNA [36], to interrogate the similarities between CM and AD further. In vivo amyloid imaging using positron emission tomography could confirm or exclude the accumulation of Aβ and tau in antemortem cases of CM. A large human study to confirm whether the APOE4 isoform is associated with CM would also be highly informative. In summary, we hypothesise that amyloidosis might be a common pathophysiological process underlying the neurological disorders of CM and AD, most likely initiated by parasite-induced co-upregulation of APOE and APP in the cerebral tissues.
Data Availability
The proteomic data reanalysed in this short communication was downloaded from the MassIVE repository under the accession number MSV000080979.
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Acknowledgements
We thank the study participants and their families for providing samples used to generate the human proteomic data reused in this manuscript.
Funding
This work was supported by grants from the Wellcome Trust: 209289/Z/17/Z (to AIA) and 203077/Z/16/Z (core grant to KEMRI-Wellcome Trust Research Programme). MK was supported by the Initiative to Develop African Research Leaders (IDeAL), part of the DELTAS Africa Initiative (DEL-15–003). For Open Access purposes, the author has applied a CC-BY public copyright licence to any author-accepted manuscript version arising from this submission. The funder had no role in study design, data collection and analysis, the decision to publish, or the writing of the manuscript.
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MK, PB and AIA conceptualised the hypothesis. MK generated the figures and wrote the first draft. SM, JMN, JAB, PB and AIA provided language revisions. All authors reviewed the final draft of the manuscript.
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The human proteomic data reanalysed in this hypothesis study had been obtained in a previous study examining CSF protein profiles of cerebral malaria and acute bacterial meningitis (using mass spectrometry) with the approval of the KEMRI Scientific Steering Committee (protocol No. 480; by Prof. Charles R. Newton).
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The parents or guardians of all study participants in the initial study had provided written informed consent during sample collection to reuse samples and data in future studies.
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Kioko, M., Mwangi, S., Njunge, J.M. et al. Linking Cerebral Malaria Pathogenesis to APOE-Mediated Amyloidosis: Observations and Hypothesis. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04366-3
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DOI: https://doi.org/10.1007/s12035-024-04366-3