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Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization.

ABSTRACT: Amyloid beta (Aβ) is a major component of amyloid plaques, which are a key pathological hallmark found in the brains of Alzheimer's disease (AD) patients. We show that statins are effective at reducing Aβ in human neurons from nondemented control subjects, as well as subjects with familial AD and sporadic AD. Aβ is derived from amyloid precursor protein (APP) through sequential proteolytic cleavage by BACE1 and γ-secretase. While previous studies have shown that cholesterol metabolism regulates APP processing to Aβ, the mechanism is not well understood. We used iPSC-derived neurons and bimolecular fluorescence complementation assays in transfected cells to elucidate how altering cholesterol metabolism influences APP processing. Altering cholesterol metabolism using statins decreased the generation of sAPPβ and increased levels of full-length APP (flAPP), indicative of reduced processing of APP by BACE1. We further show that statins decrease flAPP interaction with BACE1 and enhance APP dimerization. Additionally, statin-induced changes in APP dimerization and APP-BACE1 are dependent on cholesterol binding to APP. Our data indicate that statins reduce Aβ production by decreasing BACE1 interaction with flAPP and suggest that this process may be regulated through competition between APP dimerization and APP cholesterol binding.

SUBMITTER: Langness VF

PROVIDER: S-EPMC8098827 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Adoption of healthy lifestyle and compliance with cholesterol-lowering medication reduces the risk of cardiovascular disease (CVD). The use of digital tools and mobile technology may be important for sustaining positive behavioral change. OBJECTIVE:The primary objective of this study is to evaluate the feasibility and acceptability of administering the Cholesterol CarePlan Web app developed by the American Heart Association aimed at improving lifestyle and medication adherence among patients prescribed cholesterol-lowering medication. The secondary objective is to assess the Web app's efficacy. METHODS:A prospective, observational feasibility study will be conducted to demonstrate whether the Web app may be successfully taken up by patients and will be associated with improved clinical and behavioral outcomes. The study will aim to recruit 180 study participants being prescribed cholesterol-lowering medication for at least 30 days across 14 general practices in London, England. Potentially eligible patients will be invited to use the Web app on a smartphone and visit general practice for three 20-minute clinical assessments of blood pressure, height, weight, smoking, and nonfasting cholesterol over 24 weeks. The feasibility of administering the Web app will be judged by recruitment and dropout statistics and the sociodemographic and comorbidity profile of consenting study participants, consenting nonparticipants, and all potentially eligible patients. Acceptability will be assessed using patients' readiness to embrace new technologies, the usability of the Web app, and patient satisfaction. The efficacy of the Web app will be assessed by changes in medication adherence and clinical risk factors by levels of the Web app compliance. RESULTS:This study is currently funded by the American Heart Association. Initial study recruitment will take place between February and July 2018 followed by patient follow-up. Patient level data will be obtained in January 2019. Data analysis will be completed by February 2019. Results will be submitted for publication in March 2019. CONCLUSIONS:The potential of an app to improve patients' lifestyle and management of cholesterol may inform the design of a randomized controlled trial and the delivery of more effective CVD prevention programs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):PRR1-10.2196/9017.

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Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization.

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