Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant Aβ in plasma

Burgess, Braydon L.; McIsaac, Sean A.; Naus, Kathryn E.; Chan, Jeniffer; Tansley, Gavin; Yang, Jing; Miao, Fudan; Ross, Colin J.D.; Eck, Miranda Van; Hayden, Michael R.; Nostrand, William Van; George-Hyslop, Peter St; Westaway, David; Wellington, Cheryl L.

doi:10.1016/j.nbd.2006.06.007

Cited by 109 publications

(89 citation statements)

References 89 publications

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“…5C). Of note, in our hands, WT C57Bl/6 mice have an average plasma cholesterol level of approximately 110 mg/dl (43), indicating that the average murine CSF cholesterol concentration (0.23 mg/dl, Fig. 5C) corresponds to not more than 0.2% of that of plasma.…”

Section: Expression and Function Of Glial Lcat 891mentioning

confidence: 57%

LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins

Hirsch‐Reinshagen

Donkin

Stukas

et al. 2009

Journal of Lipid Research

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Lipid trafficking in the brain is essential for the maintenance and repair of neuronal membranes, especially after neurotoxic insults. However, brain lipid metabolism is not completely understood. In plasma, LCAT catalyses the esterification of free cholesterol on circulating lipoproteins, a key step in the maturation of HDL. Brain lipoproteins are apolipoprotein E (apoE)-containing, HDL-like particles secreted initially as lipid-poor discs by glial cells. LCAT is synthesized within the brain, suggesting that it may play a key role in the maturation of these lipoproteins. Here we demonstrate that astrocytes are the primary producers of brain LCAT. This LCAT esterifies free cholesterol on nascent apoE-containing lipopoproteins secreted from glia. ApoE is the major LCAT activator in glia-conditioned media (GCM), and both the cholesterol transporter ABCA1 and apoE are required to generate glial LCAT substrate particles. LCAT deficiency leads to the appearance of abnormal ?8 nm particles in GCM, and exogenous LCAT restores the lipoprotein particle distribution to the wild-type (WT) pattern. In vivo, complete LCAT deficiency results in a dramatic increase in apoE-HDL and reduced apolipoprotein A-I (apoA-I)-HDL in murine cerebrospinal fluid (CSF). These data show that brain LCAT esterifies cholesterol on glial-derived apoE-lipoproteins, and influences CSF apoE and apoA-I levels. In plasma, LCAT is the sole enzyme capable of esterifying cholesterol in the circulation. LCAT is a 416 amino acid protein that circulates in plasma predominately bound to lipoproteins, where it catalyses the transfer of an unsaturated fatty acid from phosphatidylcholine, or lecithin, to the free b-hydroxyl residue of cholesterol to generate cholesterol esters (CE) and lysoPC (lysolecithin) (1). Esterification of lipoprotein cholesterol results in the segregation of CE into the lipoprotein core, an essential step in peripheral HDL maturation. Mutations in the human LCAT gene underlie two distinct metabolic diseases, Familial LCAT Deficiency and Fish Eye Disease, both of which present with low HDL levels (2).The preferred plasma substrate for circulating LCAT is free cholesterol found on HDL, and apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is considered the major physiological activator of LCAT (3). In vitro experiments show that other plasma apolipoproteins, including apolipoprotein E (apoE), apoC-I, and apoA-IV, are capable of activating LCAT, albeit less efficiently than apoA-I (3). Moreover, apoA-I, and to a lesser extent, apoE appear to be the predominant in vivo activators of LCAT, as a recent analysis of apoA-I-, apoE-, and double apoA-I/ apoE-deficient mice shows that the percentage of free cholesterol esterified in plasma drops to less than 2% of wildtype (WT) values after deletion of apoA-I and apoE (4).LCAT is synthesized mainly in liver, but is also abundant in brain and testes (5-8). Indeed, brain exhibits the second highest LCAT mRNA level after liver in rats and rhesus monkeys (6, 9). Brain LCAT ...

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Section: Expression and Function Of Glial Lcat 891mentioning

confidence: 57%

LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins

Hirsch‐Reinshagen

Donkin

Stukas

et al. 2009

Journal of Lipid Research

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“…Thus, AD and vascular diseases are closely related [76]. In this sense, several studies have reported the relationships between Alzheimer's disease and high levels of lipids, principally triglycerides and cholesterol [77].…”

Section: Vascular Riskmentioning

confidence: 99%

Using direct infusion mass spectrometry for serum metabolomics in Alzheimer’s disease

2014

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Currently, there is no cure for Alzheimer's disease and early diagnosis is very difficult, since no biomarkers have been established with the necessary reliability and specificity. For the discovery of new biomarkers, the application of omics is emerging, especially metabolomics based on the use of mass spectrometry. In this work, an analytical approach based on direct infusion electrospray mass spectrometry was applied for the first time to blood serum samples in order to elucidate discriminant metabolites. Complementary methodologies of extraction and mass spectrometry analysis were employed for comprehensive metabolic fingerprinting. Finally, the application of multivariate statistical tools allowed us to discriminate Alzheimer patients and healthy controls, and identify some compounds as potential markers of disease. This approach provided a global vision of disease, given that some important metabolic pathways could be studied, such as membrane destabilization processes, oxidative stress, hypometabolism, or neurotransmission alterations. Most remarkable results are the high levels of phospholipids containing saturated fatty acids, respectively, polyunsaturated ones and the high concentration of whole free fatty acids in Alzheimer's serum samples. Thus, these results represent an interesting approximation to understand the pathogenesis of disease and the identification of potential biomarkers.

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“…The APP/PS1 transgenic mice are widely used and develop AD like amyloid plaques at the age of 36-40 weeks. Relevant to the hypothesis presented, these mice have an eight-to tenfold increase in plasma A (Burgess et al 2006). Three transgenic and four wild-type mice were anesthetized (45 mg/kg of pentobarbital), and brains were isolated, washed with PBS and segmented into right and left hemisphere.…”

Section: Tissue Collectionmentioning

confidence: 99%

Three-dimensional colocalization analysis of plasma-derived apolipoprotein B with amyloid plaques in APP/PS1 transgenic mice

Takechi

Galloway

Pallebage-Gamarallage

et al. 2009

Histochem Cell Biol

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Parenchymal accumulation of amyloid-beta (A beta) is a hallmark pathological feature of Alzheimer's disease. An emerging hypothesis is that blood-to-brain delivery of A beta may increase with compromised blood-brain barrier integrity. In plasma, substantial A beta is associated with triglyceride-rich lipoproteins (TRLs) secreted by the liver and intestine. Utilizing apolipoprotein B as an exclusive marker of hepatic and intestinal TRLs, here we show utilizing an highly sensitive 3-dimensional immuno-microscopy imaging technique, that in APP/PS1 amyloid transgenic mice, concomitant with substantially increased plasma A beta, there is a significant colocalization of apolipoprotein B with cerebral amyloid plaque. The findings are consistent with the possibility that circulating lipoprotein-A beta contributes to cerebral amyloidosis.

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Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant Aβ in plasma

Cited by 109 publications

References 89 publications

LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins

LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins

Using direct infusion mass spectrometry for serum metabolomics in Alzheimer’s disease

Three-dimensional colocalization analysis of plasma-derived apolipoprotein B with amyloid plaques in APP/PS1 transgenic mice

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