Decreased expression of the APOA1–APOC3–APOA4 gene cluster is associated with risk of Alzheimer’s disease

Abstract

BackgroundApolipoprotein is genetically associated with the risk of Alzheimer’s disease (AD). The APOA1, APOC3, and APOA4 genes are closely linked and located on human chromosome 11. Therefore, this gene cluster may be related to the risk of AD.Patients and methodsA total of 147 AD patients and 160 healthy controls were randomly recruited from June 2013 to August 2014. APOA1, APOC3, and APOA4 levels were measured using real-time quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay.ResultsAPOA1, APOC3 and APOA4 levels were significantly lower in AD patients than controls (P<0.01). APOA1, APOC3, and APOA4 levels were negatively related with the severities of AD determined by Clinical Dementia Rating scores (P<0.01). APOA1, APOC3, and APOA4 levels showed a negative relation with Montgomery–Åsberg Depression Rating Scale scores and a positive relation with RAND 36-item health-survey scores (P<0.01). There was a decreased trend for levels of APOA1, APOC3, and APOA4 in AD patients.ConclusionLow levels of APOA1, APOC3, and APOA4 are associated with risk of AD. APOA1, APOC3, and APOA4 should be developed as combined drugs for the therapy of AD.

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…Polymorphism associated with AD (Sun et al, 2005), decreased expression associated with increased risk (Lin et al, 2015) APOC4 [19 (50)] A lipid-binding lipoprotein thought to play a role in lipid metabolism Decreased expression associated with increased risk (Lin et al, 2015) ABCA7 [19 (1)] Member of the ATP-binding cassette (ABC) superfamily of transporters; catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of the membrane coupled with ATP hydrolysis, lipid homeostasis, binds APOA1, apolipoprotein-mediated phospholipid efflux from cells, cholesterol efflux, lipid raft organization Polymorphism correlate with memory impairment (Chang et al, 2019), amyloid plaque burden (Zhao Q. F. et al, 2015), cognitive impairment (Chung et al, 2014;Berg et al, 2019) ABCA1 [9 (107)] A membrane of the superfamily of ATP-binding cassette (ABC) transporters with cholesterol as its substrate, it functions as a cholesterol efflux pump in the cellular lipid removal pathway Polymorphism in AD (Chu et al, 2007;Wavrant-De Vrieze et al, 2007;Wang et al, 2013), modulates cholesterol efflux (Shibata et al, 2006;Khalil et al, 2012;Marchi et al, 2019), influences age of onset (Wollmer et al, 2003a) ABCA12 Cholesterol efflux (Hirsch-Reinshagen and Wellington, 2007;Wollmer et al, 2007;Marchi et al, 2019) LIPG [18 (43)] Diverse class of lipase enzymes includes diacylglycerol lipase (DAGL) and lipoprotein lipase (LPL) and endothelial lipase (LIPG). Hydrolyzes HDL more efficiently than other lipoproteins Polymorphism and mutation (Baum et al, 1999;Blain et al, 2006), cholesterol homeostasis (Blain and Poirier, 2004;Fidani et al, 2004), stimulation in nucleus basalis and hippocampus (Farooqui et al, 1988) (Continued) (Knebl et al, 1994;Demeester et al, 2000) SLC27A4 [9 (130)] Family of fatty acid transport proteins; translocation of long-chain fatty acids across the plasma membrane, has acyl-CoA ligase activity for long-chain and very-long-chain fatty acids (VLCFAs) SNP with p < 0.001 and significantly enriched in AD (Jones et al, 2010) NPC1 [18 (19...…”

Serum Proteomic Profiling of Obsessive-Compulsive Disorder, Washing Subtype: A Preliminary Study

“…Another function of APOA4 is as an antioxidant agent ( Qin, Swertfeger, Zheng, Hui, & Tso, 1998 ); this role may justify the accumulation of oxidative product during OCD pathophysiology ( Şimşek, Gençoğlan, & Yüksel, 2016 ). The downregulation of this protein is also reported in schizophrenia and the Alzheimer Disease (AD) ( Levin et al, 2009 ; Lin, Cao, & Gao, 2015 ). HP is another serum abundant protein that binds to hemoglobin and has chaperone function.…”

“…The complexity of OCD features made it challenging for treatment options. Most of the molecular studies in OCD are focused on genetic concept and genome-wide association studies of the disorder ( Lin, Cao, & Gao, 2015 ; Zamanian-Azodi et al, 2015 ).…”

The pleiotropic vasoprotective functions of high density lipoproteins (HDL)

“…In symptomatic AD patients, plasma apoA-I levels negatively correlate with hippocampal and whole brain volume as well as mean entorhinal cortical thickness [ 175 ] . Compared to age-matched cognitively healthy controls, levels of cerebrospinal fluid (CSF) apoA-I increase during aging but are significantly lower in AD and mild cognitive impairment patients compared to age-matched cognitively normal controls [ 176 ] . Additionally, AD patients were found to have significantly lower gene expression of APOA1 , APOC3 and APOA4 , which correlated with AD severity [ 177 ] .…”