Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease

Wollmer, M. Axel; Streffer, Johannes; Tsolaki, Magda; Grimaldi, Luigi Maria Edoardo; Lütjohann, Dieter; Thal, Dietmar Rudolf; Bergmann, Klaus von; Nitsch, Roger M.; Höck, Christoph; Papassotiropoulos, Andreas

doi:10.1038/sj.mp.4001296

Cited by 61 publications

(53 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ABCG1 is one of several genes upregulated by synthetic LXR agonists and is highly expressed in brain. Genetic studies suggest a possible role for ABCG1 in Ab metabolism, as different single nucleotide polymorphism haplotypes show either an increased or decreased odds ratio for AD risk in two European populations (80). Support for a potential role for ABCG1 in APP processing was recently provided by Tansley et al (52), who observed that ABCG1 overexpression increased Ab production 30% and increased APP processing through a-and b-secretase in HEK-APP cells.…”

Section: Discussionmentioning

confidence: 92%

ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

Burgess

Parkinson

Racke

et al. 2008

Journal of Lipid Research

View full text Add to dashboard Cite

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXRresponsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Ab production. To clarify the in vivo roles of ABCG1 in Ab metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Ab, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Ab levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Ab metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.-Burgess,

show abstract

Section: Discussionmentioning

confidence: 92%

ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

Burgess

Parkinson

Racke

et al. 2008

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Finally, use of biologically relevant, quantitative phenotypes have been proposed as a means to overcome potential clinical heterogeneity, as such quantitative traits may a) be a less heterogeneous and more direct correlate for the genetic variation(s); b) be less prone to the imprecisions of a clinical phenotype; c) be amenable to inclusion of subjects with pre-clinical disease; and d) allow for downstream functional testing of putative susceptibility variants [ 158,160,163 ]. More recently, the use of quantitative traits such as Aβ levels, mini-mental state examination scores, CSF tau levels, age-at-onset, pathological disease burden and CSF cholesterol levels [ [164][165][166][167][168] have emerged as novel approaches to study candidate AD genes.…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

Genetics of Alzheimer's Disease: A Centennial Review

2007

View full text Add to dashboard Cite

Alzheimer's disease (AD) genetics may be one of the most prolifically published areas in medicine and biology. There are nearly 200 reviews on this topic since 1991, when the first report on an autosomal dominant mutation in the amyloid precursor protein gene (APP) came out. Three earlyonset AD genes with causative mutations (APP, PS1, PS2) and one late-onset AD susceptibility gene (ApoE) exist with ample biological, genetic and epidemiological data and essentially universal acceptance about their roles in AD. Evidence from family and twin studies suggest a significant genetic component underlying AD which is not explained by the known genetic risk factors. The past 10 years in AD genetics research have led to ten independent whole genome linkage and association studies with implications for multiple genomic areas for harboring AD susceptibility genes. To date, there are about 900 papers reporting associations between variations in more than 350 genes spread over 23 autosomes. One hundred years after the first published article on Alzheimer's disease, much is known about the pathophysiology of this disease, however much more remains to be discovered about its etiology. This review summarizes the evidence for the genetic component in AD, identification of the early-onset familial AD genes and ApoE, and the current state of knowledge for additional AD susceptibility loci and alleles. The future directions for genetic research in Alzheimer's disease as a common and complex condition are also discussed.

show abstract

“…87 A polymorphism in the ACAT gene (the A/A genotype of rs1044925) that results in low brain cholesterol content has been associated with low brain amyloid load and a reduced risk for AD in European populations. 88 ACAT inhibitors have been widely studied for the treatment of atherosclerosis, and may prove equally important for the treatment and prevention of AD. However, the exact mechanism by which CE levels modulate the generation of Ab is not known.…”

mentioning

confidence: 99%

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

et al. 2006

View full text Add to dashboard Cite

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E e4 (APOE e4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Ab clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE e4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE e4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.

show abstract

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease

Cited by 61 publications

References 18 publications

ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

Genetics of Alzheimer's Disease: A Centennial Review

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

Contact Info

Product

Resources

About