Research Paper

Ezetimibe lowers risk of Alzheimer’s and Related Dementias over 7-fold, reducing aggregation in model systems by inhibiting 14-3-3G::hexokinase interaction

Authors

Akshatha Ganne ², Nirjal Mainali ^1,2, Meenakshisundaram Balasubramaniam2, Ramani Atluri², Sonu Pahal^1,2, Joseph Asante^1,2, Corey Nagel⁴, Srikanth Vallurupalli ^3,5,Robert J. Shmookler Reis^1-3, and Srinivas Ayyadevara^1-3

¹Bioinformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock AR 72205

²Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, Little Rock AR 72205

³Central Arkansas Veterans Healthcare System, Little Rock AR 72205

⁴College of Nursing, University of Arkansas for Medical Sciences, Little Rock AR 72205

⁵Department of Internal Medicine, Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Correspondence:
Robert J. Shmookler Reis, Reynolds Institute on Aging, 629 Jack Stephens Drive, Little Rock AR, USA 72205. Tel.: 501-526-5820; email: rjsr@uams.edu

Srinivas Ayyadevara, Reynolds Institute on Aging, 629 Jack Stephens Drive, Little Rock AR, USA 72205. Tel.: 501-526-7282; email: AyyadevaraSrinivas@uams.edu

Article |  PDF 

Abstract

Numerous factors predispose to progression of cognitive impairment to Alzheimer’s disease and related dementias (ADRD), most notably age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes, and Down’s syndrome. Protein aggregation is diagnostic for neurodegenerative diseases, and may be causal through promotion of chronic neuroinflammation. We isolated aggregates from postmortem hippocampi of ADRD patients, heart-disease patients, and age-matched controls. Aggregates, characterized by high-resolution proteomics (with or without crosslinking), were significantly elevated in heart-disease and ADRD hippocampi. Hexokinase-1 (HK1) and 14-3-3G/γ proteins, previously implicated in neuronal signaling and neurodegeneration, are especially enriched in ADRD and heart-disease aggregates vs. controls (each P<0.008), and their interaction was implied by extensive crosslinking in both disease groups. Screening the hexokinase-1::14-3-3G interface with FDA- approved drug structures predicted strong affinity for ezetimibe, a benign cholesterol- lowering medication. Diverse cultured human-cell and whole-nematode models of ADRD aggregation showed that this drug potently disrupts HK1::14-3-3G adhesion, reduces disease-associated aggregation, and activates autophagy. Mining clinical databases supports drug reduction of ADRD risk, decreasing it to 0.14 overall (P<0.0001; 95% C.I. 0.06–0.34), and <0.12 in high-risk heart-disease subjects (P<0.006). These results suggest that drug disruption of the 14-3-3G::HK1 interface blocks an early “lynchpin” adhesion, prospectively reducing aggregate accrual and progression of ADRD.