Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.

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Recently, the amyloid hypothesis of Alzheimer's disease has been questioned

Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.

The ε4 variant of apolipoprotein E is the strongest and most common genetic risk factor for Alzheimer's disease. However, the E4 variant does not correlate with risk in every population. Women are more likely to develop AD than men across most ages and APOE genotypes.

While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease.

In this new publication the authors determined the concurrent effects of systemic metabolic changes and brain inflammation in young and aged male and female mice carrying the APOE4 gene.

Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, the authors found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of Alzheimer's disease proteinopathies.

Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines. The authors found that these signatures are APOE genotype dependent.

They propose that, because APOE4 is present from birth and has been shown to have deleterious effects on immune function and metabolism well before the age of AD onset, long-term APOE4-driven systemic and brain immunometabolic effects can provoke an AD-inducible environment independent of interactions with Aβ or tau.

The authors determine that aging-related cytokine patterns in the hippocampus can predict systemic metabolic outcomes of young and aged humanized APOE3 and APOE4 male and female mice. Specifically, they uncover unique patterns of cytokines in APOE3 versus APOE4 mice that correlate with body adiposity, glucose tolerance, and insulin sensitivity. Male and female mice exhibit differing cytokine signatures that correlate with peripheral metabolic function, emphasizing important sex differences in biomarker outcomes.

In its proposed role as a controller of glucose metabolism, altered hippocampal immune signaling could be the stimulus for APOE variant-specific differences in adiposity and glucose tolerance.

Alternatively, peripheral changes in adiposity, glucose tolerance, and insulin sensitivity may impact hippocampal cytokine levels through upregulation of factors that can pass the blood-brain barrier, or through affecting vascular integrity and allowing infiltration of peripheral immune cells and signaling molecules.

Most likely, both of these scenarios could be occurring simultaneously.

The authors' results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.

Some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.

Read the original article on Pubmed

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