Moreover mice exposed to high cholesterol diet have mildly a

Moreover, mice exposed to high-cholesterol diet have mildly activated astrocytes, increased expression of ApoE and aquaporin-4 in the hippocampus, and altered levels of proteins associated with Aβ metabolism (Chen et al., 2016), which is related to a higher demand for cholesterol transport and the need to remove the soluble Aβ (Czuba et al., 2017). An increase in APP-processing enzyme in mice lacking LDLR under high-cholesterol diet and an increased accumulation of Aβ in mice lacking LDLR were also reported (Thirumangalakudi et al., 2008). ApoE is crucial in the regulation of cholesterol levels and in Aβ degradation by microglial cells (Lee et al., 2012). It also regulates macrophage-induced phagocytosis in the periphery (Grainger et al., 2004, Baitsch et al., 2011). As previously reported, genetic variations of ApoE can induce both systemic and CNS inflammation, through increased release of proinflammatory cytokines (Lynch et al., 2003, Cudaback et al., 2015), also overproduced in hypercholesterolemia (Chen et al., 2016). In transgenic mice co-expressing five familial AD mutations, the presence of human ApoEε4 allele increases inflammatory response induced by Aβ, represented by increased microglial activation and on the table IL-1β levels (Rodriguez et al., 2014). The expression of human ApoEε4 in mice, but not ApoEε2 or 3, leads to BBB disruption through the activation of the proinflammatory pathway CypA-NFκB-matrix-metalloproteinase-9, which increases neurodegeneration due to invasion of neurotoxic proteins from the periphery (Bell et al., 2012). Furthermore, in ApoEε4 transgenic mice, the activation of amyloid cascade induces microgliosis and astrogliosis (Belinson and Michaelson, 2009). Thus, the presence of ApoEε4 isoform contributes to the inflammatory response in AD. The plasmatic increase in LDL also induces BBB disruption (Dias et al., 2015), facilitating the invasion of immune cells and contributing to neuroinflammation (Chen et al., 2008) and to the pathogenesis of AD (Chen et al., 2014). In the brain, Aβ can bind to LDLRs expressed in glial cells that mediate internalization of the peptide into lysosomes. However, changes in LDLRs expression in astrocytes alter this clearance (Basak et al., 2012). AD transgenic mice that lack LDLR have increased senile plaques deposition and reduced astrocytosis and microgliosis. Thus, LDL pathways play an important role in the immune response modulated by glial cells in AD (Katsouri and Georgopoulos, 2011). Despite the brain cholesterol being produced mainly by de novo synthesis, many studies have demonstrated that low HDL plasma levels correlate with AD risk and are present in AD patients; while high HDL levels are protective against AD (Van Lenten et al., 1995, Khalil et al., 1998, Khalil et al., 2012, Vitali et al., 2014). The neuroprotective effects of HDL were reported in rat models of stroke, in which the therapy with recombinant HDL reduced neuronal damage and stress-induced ROS levels (Paterno et al., 2004). Treatment of an AD transgenic mouse model with a mimetic peptide of apolipoprotein A-I (the main protein component of HDL) in association with pravastatin improved cognition and decreased Aβ deposition in the brain, and decreased the expression of neuroinflammatory markers (Handattu et al., 2009). Overexpression of the apolipoprotein A-I itself also prevents memory deficits and attenuates neuroinflammation and amyloid angiopathy in an AD transgenic mouse model (Lewis et al., 2010b). It has been shown that small particles of HDL can cross the BBB (Balazs et al., 2004), which might allow the plasmatic lipoprotein levels to influence brain cholesterol homeostasis (Vitali et al., 2014). Once HDL has anti-inflammatory and anti-oxidant properties (Barter et al., 2004, Vitali et al., 2014), it might influence neuroinflammation and oxidative stress present in AD. Cholesterol-lowering drugs may influence neuroinflammation in AD, as mentioned above. Since statins inhibit HMG-CoA reductase, they disrupt not only the synthesis of cholesterol products, but also isoprenoids, thus preventing protein isoprenylation. Both these processes influence how APP trafficking occurs. It has been demonstrated that a decrease in cholesterol levels induced by statins decreases Aβ synthesis, favoring the non-amyloidogenic processing of APP, whereas reduction in isoprenoids levels favors the accumulation of APP and Aβ (Cole et al., 2005, Ostrowski et al., 2007). A decrease in Aβ synthesis induced by statins may inhibit activation of immune cells such as microglia, preventing AD-associated inflammation (Silva et al., 2013). Therefore, the anti-inflammatory activity of these drugs is not only dependent on their cholesterol-lowering mechanism (Bu et al., 2011).