Apolipoprotein E4 (ApoE4) is the major genetic risk factor for late-onset Alzheimer’s disease (AD) (Strittmatter et al., 1993). However, not all ApoE4 carriers develop AD, even among those who exceed 90 years of age (Tanzi, 1999). It has been reported that the ApoE isoform (ApoE2 > ApoE3 > ApoE4) affects the clearance of amyloid-β (Aβ), a major component of AD pathology, from the brain (Castellano et al., 2011). In addition, ApoE bound to Aβ is internalized through the cell surface ApoE receptor low-density lipoprotein receptor-related protein (LRP)1 (LaDu et al., 1994). LRP1 also has effects on Aβ clearance in vascular smooth muscle cells and transport across the blood brain barrier in APP/PS1 mice (Kanekiyo et al., 2012, Pflanzner et al., 2011). All these findings suggest that brain ApoE protein and ApoE-LRP1 binding play some roles in AD pathogenesis; however, it is unclear whether peripheral ApoE influences AD pathology formation in the brain through LRP1 binding. Since LRP1 can modulate immune responses via proinflammatory cytokines and microglial activation in the brain (Yang et al., 2016), it is probable that peripheral ApoE and ApoE-LRP1 binding are involved in brain AD pathogenesis by regulating inflammatory processes.

Multiple studies have reported that circulating ApoE levels determined by ApoE genotypes (Mooijaart et al., 2006, Marais, 2019). Importantly, using the ApoE target replacement (TR) mouse models, the human E4 allele impacts the low levels of ApoE protein both in blood and brain, and the dominant negative effect on cognitive ability (Johnson et al., 2014, Lane-Donovan and Herz, 2016). In addition, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes cognitive disability only in ApoE4, but not in ApoE3, mice (Torres et al. 2020). Our study used data from the Framingham Heart Study (FHS) offspring cohort and found that chronically elevated C-reactive protein (CRP) levels in blood are associated with an increased risk of AD in ApoE4 carriers but not in ApoE3 or ApoE2 carriers (Tao et al., 2018). ApoE protein, like CRP, is mainly produced by the liver and is released into the blood when systematic inflammation occurs. We aimed to study whether peripheral ApoE and its binding to LRP1 protect against AD pathogenesis in the brain when peripheral CRP levels are elevated. As systemic chronic low-grade inflammation is a modifiable and potentially treatable medical condition, identifying and characterizing whether ApoE and CRP play interacting roles leading to AD in ApoE4 carriers is useful for prevention of and intervention in the disease.

CRP is a protein that plays a role in the immune response to toxins or injuries in systemic inflammation and is used to monitor peripheral chronic low-grade inflammation in clinical practice (Stephensen and Gildengorin, 2000). There are two forms of CRP (Slevin and Krupinski, 2009): 1) native CRP (pCRP) is a pentameric oligoprotein and an acute phase reactant that is produced during active inflammatory reactions; and 2) monomeric CRP (mCRP), or free subunits of pCRP, is produced during the acute phase and more so during a chronic phase by the irreversible dissociation of pCRP (Potempa et al., 2015). mCRP has a much lower aqueous solubility and can cause tissue damage (Caprio et al., 2018). CRP levels increase with age (Stephensen and Gildengorin, 2000, Tang et al., 2017), probably because infections of the respiratory, gastrointestinal, and urinary tract systems are more likely to occur in the elderly and induce chronic low-grade inflammation. mCRP has been shown to play a role in the pathogenesis of cardiovascular diseases (Wang et al., 2015), age-related macular degeneration (Chirco et al., 2016), and poststroke inflammation (Slevin et al., 2010). In one study, mCRP was directly injected into the hippocampus of an AD mouse model, 3×Tg, and it was found that mCRP injection increased the severity of AD pathology in the brain (Slevin et al., 2015). In this study, we hypothesized that elevation of peripheral mCRP levels induces/enhances AD pathology in the brain, whereas blood ApoE and ApoE-LRP1 binding antagonize mCRP to promote AD pathogenesis in the brain during peripheral chronic low-grade inflammation. We used human data as well as different ApoE knock-in and ApoE-/- mice to characterize the relationship between peripheral ApoE, ApoE-LRP1 binding, and AD pathogenesis in the brain in the absence and presence of elevated blood mCRP levels.