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

Over 6.2 million Americans are currently living with Alzheimer's disease (AD), a neurodegenerative disease manifesting as cognitive decline and memory loss (Alzheimer's Association, 2021). While aging is the greatest overall risk factor for development of AD, the strongest and most common genetic risk factor is the ε4 variant of apolipoprotein E (APOE4) (Corder et al., 1993). The APOE gene has 3 isoforms, ε2, ε3, and ε4, with allelic frequencies of 7%, 79%, and 14% in the US population, respectively (Lanfranco et al., 2020). APOE4 carriers have a dose-dependent 3–14-fold increased risk over APOE3 carriers for developing AD (Lanfranco et al., 2020); however, the physiological mechanism of this conveyed risk is not yet fully understood.

In addition to promoting onset and progression of AD, APOE4 is associated with inflammatory processes and outcomes in both the brain and the periphery, including increased low-density lipoprotein (LDL) cholesterol, increased incidence of cardiovascular disease, and promotion of metabolic syndrome (Bennet et al., 2007; El-Lebedy et al., 2016; Lagging et al., 2019; Lahoz et al., 2001; Torres-Perez et al., 2016; Tsuang et al., 2013). As a genetic variant, APOE4 is a risk factor that carriers possess from birth, with effects potentially building over their lifetime (Fernandez et al., 2019). Thus, many APOE4-related changes, such as increased inflammation (Jofre-Monseny et al., 2008; Wang et al., 2020) and metabolic dysfunction (Jagust et al., 2012; Wu et al., 2018; Zhao et al., 2017), likely occur before the age at which the hallmark AD proteinopathies, amyloid-β (Aβ) plaques and neurofibrillary tau tangles, form in the brain. However, the majority of the focus for APOE AD research has been on the interaction of APOE4 with Aβ and tau, despite the appearance of appreciable amounts of these pathological proteins only later in life (Huynh et al., 2017; Litvinchuk et al., 2021; Liu et al., 2017; Martínez-Martínez et al., 2020; Shi et al., 2017). We 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 (Flowers and Rebeck, 2020), long-term APOE4-driven systemic and brain immunometabolic effects can provoke an AD-inducible environment independent of interactions with Aβ or tau.

APOE4 alters lipid (Lin et al., 2018; Vardarajan et al., 2020), cholesterol (Lin et al., 2018), and glucose metabolism in the brain (Farmer et al., 2021; Qi et al., 2021; Wu et al., 2018; Zhao et al., 2017), yet little is known about the influence of systemic metabolic function on molecular signaling networks in the brain in the context of APOE4 (Christensen and Pike, 2019; Jones et al., 2019; Moser and Pike, 2017). Previous studies have identified a link between systemic metabolism and hippocampal electrophysiology changes (Seto et al., 1983; Tingley et al., 2021), where communication between the hippocampus and periphery can involve hippocampal signaling to the pancreas and liver, as well as to the hypothalamus (Lathe, 2001; Tingley et al., 2021), a major metabolic control center in the brain. A recent study from Guojun Bu's group even identified that liver-expressed APOE in mice could affect cognition and synaptic function (Golden and Johnson, 2022; Liu et al., 2022), indicating the importance of peripheral APOE effects on the brain. An approach that identifies the relationships of APOE4 effects on systemic metabolic function and neuroinflammation together, instead of studying the brain and periphery as isolated systems, is necessary to define the disease-promoting environment created by the interacting effects of systemic metabolic dysfunction and neuroinflammation under the combined influence of APOE genotype and aging.

Here, we 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, we 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. Our results highlight a potential mechanism by which APOE4 alters cytokine levels in the hippocampus, which may create an environment promoting the formation of AD pathology. Our newfound correlations between peripheral metabolic markers and cytokine signatures based on APOE genotype suggest a valuable opportunity for future AD biomarker development.

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