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  • Aberrant lipid levels are associated with various disorders

    2024-04-16

    Aberrant lipid levels are associated with various disorders, including vascular diseases and diabetes. Furthermore, important events support the idea that lipids, especially cholesterol and its derivatives, have a fundamental role in the physiopathology of AD. The 3-Indolebutyric acid mg is rich in cholesterol, and it has 3-Indolebutyric acid mg been shown that lipids are involved in neuronal function and synaptic plasticity (Pfrieger, 2003). Increased levels of cholesterol and its derivatives in the brain induce neuronal apoptosis, oxidative stress and tau hyperphosphorylation (McLaurin et al., 2003, Ma et al., 2010). Moreover, the lipid profile of the cell membrane is crucial for the activity of enzymes involved in APP processing and Aβ production. High ratios between membrane and endosomal cholesterol levels can affect membrane microdomains where enzymes are localized, inducing a misbalance in APP processing and favoring the amyloidogenic pathway (Wahrle et al., 2002, Osenkowski et al., 2008, Brown and Bevan, 2017, Sun et al., 2017). Follow-up studies with patients have shown that high levels of serum cholesterol in mid-life are associated with an increased risk for developing AD in late life (Whitmer et al., 2005, Solomon et al., 2009). In contrast, Mielke and colleagues (2005) examined the total serum cholesterol levels in late-life patients diagnosed with AD and found an association between high cholesterol levels in late life with reduced risk of dementia (Mielke et al., 2005). These discrepancies can be explained by the variables in the studies, such as the protocols used and the age of the subjects. Indeed, it seems that high cholesterol is associated with risk for AD when its levels are changed in early life, years before the onset of neurodegenerative disease (Mielke et al., 2005, Whitmer et al., 2005, Solomon et al., 2009). During neurodegeneration, BBB deregulation leads to the disruption of cholesterol homeostasis in the brain, which could contribute to AD pathology. Post-mortem analysis indicates that the senile plaques of AD patients have significantly elevated levels of cholesterol (Panchal et al., 2010). Additionally, as previously mentioned, the amount of cholesterol may affect APP-processing enzymes. In vitro studies reported that cellular and membrane cholesterol can alter the activity of enzymes, such as secretases, and significantly increase Aβ production (Abad-Rodriguez et al., 2004). In animal models, hypercholesterolemia increases the severity of Aβ-induced pathologies. A cholesterol-rich diet prior to Aβ peptide injection enhances immunoreactivity of Aβ and phosphorylated tau, as well as deficits in learning and memory (Park et al., 2013). Moreover, hypercholesterolemic LDLR knock-out mice exhibit cognitive deficits, changes in memory-associated genes and hippocampal mitochondrial dysregulation (de la Monte and Tong, 2014, de Oliveira et al., 2014). It is not surprising that molecules involved in the cholesterol metabolic pathway are involved in the development of AD. Some of these molecules, like apolipoprotein E (ApoE), sortilin-related receptor (SORL1) and ABC subfamily A (ABCA), are strongly associated with the risk to develop the disease. ApoE is the most abundant apolipoprotein in the CNS and has an important role in cholesterol transport between cells within the CNS (Corder et al., 1993). Studies have shown that different isoforms of ApoE can influence Aβ aggregation and clearance, and may also modulate neurotoxicity and tau phosphorylation (Kim et al., 2009, Holtzman et al., 2012). Aβ deposition is significantly increased in the brain of ApoE-deficient mice compared to controls (DeMattos et al., 2004). Allelic variations in the ApoE gene may facilitate Aβ deposition and oligomerization, and increase about 10-fold the risk of AD (Corder et al., 1993, Serrano-Pozo et al., 2011). While the ApoE-ε2 allelic variant is protective against AD, the ApoE-ε4 allele represents a risk factor for the disease. In fact, up to 60% of AD patients carry at least one ε4 allele, which increases Aβ deposition in the form of senile plaques (Farrer et al., 1997, Reiman et al., 2009, Liu et al., 2013). The isoform of ApoE present in the brain also influences Aβ clearance. The ApoE-ε3 isoform, for example, facilitates Aβ clearance across the BBB, when compared with the ApoE-ε4 (Bachmeier et al., 2013). The functional differences of each isoform are related to their action at the lipoprotein receptor, which modifies Aβ elimination (Bachmeier et al., 2014). It is important to mention that obesity induced by western diet (47% fat, 17% sucrose) can accelerate AD-related pathology in a mouse model that combines familial AD transgenes with human APOE-ε4, but not in the presence of APOE-ε3 (Moser and Pike, 2017).