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  • Recent genome wide association studies have indicated SORL

    2024-04-03

    Recent genome-wide association studies have indicated SORL1 as a risk factor for AD (Meng et al., 2007, Rogaeva et al., 2007, Wen et al., 2013). SORL1, is expressed in neurons (Yin et al., 2015) and also regulates APP traffic from the cell membrane to the Golgi apparatus. A reduction in its expression leads to an accumulation of Aβ (Yancey et al., 2003). The interaction between SORL1 and ApoE has also been associated with AD and with the increase in Aβ concentration in cerebrospinal fluid (CSF) of patients (Shen et al., 2017). It has been reported that ABC transporters protect the Trehalose against Aβ deposition by controlling its production or clearance (Abuznait and Kaddoumi, 2012). ABCA members are membrane transporters expressed in various cell types. They are involved in cholesterol efflux through interaction with apolipoproteins carrying cholesterol, which avoids the lipid intracellular accumulation (Koldamova et al., 2005). In an AD animal model, ABCA1 deficiency results in significantly higher deposition of Aβ in the brain and reduced levels of ApoE, both of which contribute to the neurodegenerative process in these animals (Koldamova et al., 2005). In humans, cholesterol efflux mediated by ABCA1 is reduced in the CSF of patients with mild cognitive impairment (MCI) and AD (Yassine et al., 2016). Furthermore, mutations in the ABCA1 gene are associated with lower plasma levels of ApoE and significantly increased risk of vascular disease (Nordestgaard et al., 2015). Similar to ABCA1, genetic studies show that ABCA2 variant is linked to the risk of sporadic AD (Wollmer et al., 2006). ABCA7, another member of the family, is highly expressed in the brain and helps APP processing (Chan et al., 2008, Kim et al., 2013, Sakae et al., 2016), while its loss of function in cell lines and deficiency in mouse models of AD accelerates Aβ generation and the pathology progression (Satoh et al., 2015, Sakae et al., 2016). Accordingly, genetic variants of ABCA7 may affect intramembrane transport of cholesterol-associated molecules (Chan et al., 2008). Thus, there is an increasing interest in the potential therapeutic value of the modulation of ABC transporters in AD (Pahnke et al., 2014). HDL regulates reverse cholesterol transport through the human body, removing cholesterol from cells through its interaction with ABCA1 (Hottman et al., 2014). Several lines of evidence suggest that HDL has a protective role against AD. For example, in a prospective cohort study with 1130 healthy elderly participants, Reitz and colleagues showed that higher HDL levels are associated with reduced risk for dementia (Reitz et al., 2010). Low HDL levels have been associated with an increased risk to develop AD (Ancelin et al., 2013) as well as with the course of the disease (Chen et al., 2014, Reed et al., 2014). In an animal model of AD, therapy with HDL injection significantly reduced Aβ levels (Robert et al., 2016). These data suggest that therapies targeting HDL can be important tools for the treatment of dementia. In contrast to HDL, LDL mediates cholesterol transport to the tissues. Therefore, it has been strongly implicated in injuries associated with cholesterol metabolism. Many studies have shown that increased serum LDL is associated with Aβ deposition in the brain (Lesser et al., 2011, Reed et al., 2014) and increased risk to develop AD (Kuo et al., 1998, Solomon et al., 2009). Since elevated plasmatic cholesterol can induce BBB disruption (Perry et al., 2003, Chen et al., 2008), peripheral blood cells, such as macrophages, can invade the brain parenchyma, contributing to the neuroinflammatory response that occurs in AD and inducing activation of microglia and astrocytes (Chen et al., 2008, Thirumangalakudi et al., 2008), as explained later in this review. Triglycerides are the major form of fat in humans and other animals. In contrast to cholesterol, plasma levels of triglycerides do not seem to be associated with AD (Ramdane and Daoudi-Gueddah, 2011). Accordingly, several studies demonstrated no changes in triglycerides levels in AD patients (Reitz et al., 2004, Li et al., 2008, Cunnane et al., 2012, Mielke et al., 2012, Proitsi et al., 2014, Clarke et al., 2015). Moreover, fatty acids, which form triglycerides, can mediate endocytosis of ApoE-containing proteins, through the lipolysis-stimulated lipoprotein receptor (LSR). Since this receptor is paramount for controlling the levels of ApoE-containing proteins, its reduced expression worsens both dyslipidemia and AD-associated features in a mouse model (Pincon et al., 2015). In addition, therapies with medium-chain triglycerides are being studied for the treatment of mild to moderate AD (Sharma et al., 2014, Kimoto et al., 2017).