Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content

Racchi, Marco; Baetta, Roberta; Salvietti, Nathalie; Ianna, Paola; Franceschini, Guido; Paoletti, Rodolfo; Fumagalli, R.; Govoni, Stefano; Trabucchi, Marco; Soma, Maurizio R.

doi:10.1042/bj3220893

Cited by 150 publications

(101 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…McLaurin et al 44 reported that membrane cholesterol inversely correlated with the extent of Ab 1 -40 and Ab 1 -42 bilayer interaction and Gibson-Wood et al 45 found that distribution of cholesterol rather than the total mass is what regulates Ab genesis. Racchi et al 46 showed that membrane sterol enrichment by incubation with cholesterol-rich b-VLDL caused a dose-dependent inhibition of Ab release. In transgenic mice expressing the Swedish familial AD mutations, changes in concentrations of sAPP and Ab in brain were all negatively correlated with serum cholesterol concentrations.…”

Section: Discussionmentioning

confidence: 99%

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment

et al. 2008

View full text Add to dashboard Cite

Background: Plasma amyloid b-peptide (Ab) can compromise the blood-brain barrier, contributing to cerebrovascular alterations and amyloid angiopathy in Alzheimer's disease (AD). The objectives of this study were to investigate the distribution of lipoprotein-bound plasma-Ab isoforms.Methods: This involved a case-control study of subjects with AD or amnestic mild cognitive impairment (MCI) versus controls. Lipoprotein Ab distribution was determined in fasted plasma. For assessment of chylomicron homeostasis in the postabsorptive state, subjects were bled 4 h after a low-fat meal. The main outcome measures were plasma lipoprotein Ab isoform distribution and lipid homeostasis. Results: We found the majority of plasma Ab to be associated with triglyceride-rich lipoproteins (TRLs) encompassing chylomicrons, VLDL and IDL. For all lipoprotein groups, Ab 1 -40 was the predominant isoform, accounting for approximately 50% of the total. Thereafter, equivalent amounts of the isoforms 1 -42, 2-40, 1 -38, 1-37 and 1 -39 were found. Ab 1 -37 , Ab 1 -38 and Ab 2 -40 isoforms were significantly enriched within the TRL fraction of AD/MCI subjects and similar trends were observed for isoforms Ab 1 -39 , Ab 1 -40 and Ab 1 -42 . Lipoprotein-Ab was inversely associated with plasma total-and LDL cholesterol. AD/MCI subjects were not dyslipidaemic, however, there was evidence of accumulation of chylomicrons in the postabsorptive state. Conclusions: Our data show that Ab was found to be associated with plasma lipoproteins, especially those enriched with triglyceride. We find that Ab may be increased in normolipidaemic AD subjects, commensurate with possible disturbances in postprandial lipoprotein homeostasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment

et al. 2008

View full text Add to dashboard Cite

show abstract

“…CV, isolated from fresh eggs, were treated with cinnamycin and neomycin for 30 min (25°C) followed by fusion assays. For fusion recovery, CV suspensions (OD 405 1.0), isolated from Smst-/Atst-incubated eggs, were treated with 2 mM CHOL-loaded hpβcd or 200 μM αT for 30 min (25°C), centrifuged, and suspended in fresh BIM for fusion assays; CHOL-loaded hpβcd was prepared as described [27,42,70]. αT was delivered in hexadecane (<0.1% solvent, final) [26,27].…”

Section: Egg Manipulationsmentioning

confidence: 99%

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Rogasevskaia

Coorssen

2011

J Chem Biol

View full text Add to dashboard Cite

Studies using isolated sea urchin cortical vesicles have proven invaluable in dissecting mechanisms of Ca 2+ -triggered membrane fusion. However, only acute molecular manipulations are possible in vitro. Here, using selective pharmacological manipulations of sea urchin eggs ex vivo, we test the hypothesis that specific lipidic components of the membrane matrix selectively affect defined late stages of exocytosis, particularly the Ca 2+ -triggered steps of fast membrane fusion. Egg treatments with cholesterol-lowering drugs resulted in the inhibition of vesicle fusion. Exogenous cholesterol recovered fusion extent and efficiency in cholesterol-depleted membranes; α-tocopherol, a structurally dissimilar curvature analogue, selectively restored fusion extent. Inhibition of phospholipase C reduced vesicle phosphatidylethanolamine and suppressed both the extent and kinetics of fusion. Although phosphatidylinositol-3-kinase inhibition altered levels of polyphosphoinositide species and reduced all fusion parameters, sequestering polyphosphoinositides selectively inhibited fusion kinetics. Thus, cholesterol and phosphatidylethanolamine play direct roles in the fusion pathway, contributing negative curvature. Cholesterol also organizes the physiological fusion site, defining fusion efficiency. A selective influence of phosphatidylethanolamine on fusion kinetics sheds light on the local microdomain structure at the site of docking/fusion. Polyphosphoinositides have modulatory upstream roles in priming: alterations in specific polyphosphoinositides likely represent the terminal priming steps defining fully docked, release-ready vesicles. Thus, this pharmacological approach has the potential to be a robust high-throughput platform to identify molecular components of the physiological fusion machine critical to docking, priming, and triggered fusion.

show abstract

“…by statin treatment) causes both an increase in the secretion of soluble APP (sAPP, a-secretase product) and a decrease in Ab production. 67,[69][70][71] Increasing membrane cholesterol decreases the secretion of sAPP, 72,73 possibly due to cholesterol interfering with glycosylation in the protein secretory pathway. 74 As sAPP is thought to have neurotrophic properties, decreasing sAPP levels may promote neurodegeneration.…”

Section: Cholesterol and Cad As Ad Risk Factorsmentioning

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

Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content

Cited by 150 publications

References 53 publications

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

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

Contact Info

Product

Resources

About