Immunoinflammatory role of apolipoprotein E4 in malnutrition and enteric infections and the increased risk for chronic diseases under adverse environments

Abstract

Apolipoprotein E plays a crucial role in cholesterol metabolism. The immunomodulatory functions of the human polymorphic APOE gene have gained particular interest because APOE4, a well-recognized risk factor for late-onset Alzheimer's disease, has also been recently linked to increased risk of COVID-19 infection severity in a large UK biobank study. Although much is known about apoE functions in the nervous system, much less is known about APOE polymorphism effects on malnutrition and enteric infections and the consequences for later development in underprivileged environments. In this review, recent findings are summarized of apoE’s effects on intestinal function in health and disease and the role of APOE4 in protecting against infection and malnutrition in children living in unfavorable settings, where poor sanitation and hygiene prevail, is highlighted. The potential impact of APOE4 on later development also is discussed and gaps in knowledge are identified that need to be addressed to protect children's development under adverse environments.

ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers

“…Corroborating with this findings, apoE protein levels are lower in patients with sepsis [105]. Although this is a compelling possibility, the complex apoE-HDL or HDL alone (or other plasmatic lipoproteins) may also have a role in diminishing LPS [106,107]. Other biological interactions, such as those with the innate immune system, are still relatively unexplored and require further investigation.…”

“…Intriguing is the finding that APOE4 is associated with low c-reactive protein blood levels and pro-inflammatory innate responses in gather-hunter populations living in remote areas of the Amazon [119,120] under highly contaminated environments. APOE4 is now being considered a gene candidate for antagonistic pleiotropy over human evolutionary changes, and enteric helminths may be the strongest driving force for keeping APOE4 in our genetic pool despite its deleterious effects during aging under modern western lifestyles [106,121]. Infectious diseases and famine have been recognized as strong driving forces to shape our genome during human evolution and the modernity era [122,123].…”

“…Thus, the design of apoE mimetic peptides of protective isoforms seems to be a promising approach in CNS disorders. In recent years, studies have demonstrated that apoE mimetic peptides have played a beneficial role in different experimental models by modulating the expression of pro-inflammatory cytokines in the body and the brain [106].…”

Risk Factors for Severe COVID-19 and Hepatitis C Infections: The Dual Role of Apolipoprotein E4

“…Findings of APOE4 deleterious effects on COVID-19 outcomes have been identified in UK biobank studies enrolling patients living in developed settings; however, there is a gap of knowledge whether this potential effect could be replicated in populations living under adverse environments, as APOE4 could have a different role in such conditions ( 42 – 44 ). In addition, APOE4 may be relevant in affecting long COVID-19 cardiovascular sequelae in risk groups ( 45 ), which raises public health concerns.…”