 Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production_Mark A. Lovell

Research ArticleCalcium Channel Blockers, Progression to Dementia,and Effects on Amyloid Beta Peptide ProductionMark A. Lovell, 1,2 Erin Abner, 2,3 Richard Kryscio, 2,4 Liou Xu, 5Shuling X. Fister, 2 and Bert C. Lynn 1,21 Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA2 Sanders-Brown Center on Aging and Alzheimer’s Disease Center, University of Kentucky, Lexington, KY 40536, USA3 Department of Epidemiology, University of Kentucky, Lexington, KY 40506, USA4 Departments of Statistics and Biostatistics, University of Kentucky, Lexington, KY 20536, USA5 National Minority Quality Forum, Washington, DC 20005, USACorrespondence should be addressed to Mark A. Lovell; malove2@uky.eduReceived 22 February 2015; Revised 5 June 2015; Accepted 8 June 2015Academic Editor: Ada PopoloCopyright © 2015 Mark A. Lovell et al. T h is is anopen access article distributedunder the Creative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine ifsubjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminishedprogression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia forsubjects who used any of the f i ve common categories of antihypertensive drugs to those with similar demographic characteristicsbut who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) butnot the other classes of antihypertensives showed a signif i cant decrease in the rate of progression to dementia. Signif i cantly, use ofCCBsamelioratedthenegativeef f ectsofthepresenceofAPOE-4allelesoncognitivedecline.TodetermineifCCBscouldminimizemyloidbetapeptide(A𝛽 1–42 )production,H4neurogliomaculturestransfectedtooverexpressAPPweretreatedwithvariousCCBsand A𝛽 1–42 levels and levels of proteins involved in A𝛽 production were quantif i ed. Results show that treatment with nifedipine ledto a signif i cant decrease in levels of A𝛽 1–42 , with no signif i cant decrease in cell viability. Collectively, these data suggest that use ofCCBs signif i cantly diminishes the rate of progression to dementia and may minimize formation of A𝛽 1–42 .1. IntroductionAlzheimer’s disease (AD) is the 6th leading cause of deathin the United States and today af f ects 5.2 million Americansaged 65 and more [1]. Without preventive strategies or devel-opment of an ef f i cacious treatment, there may be 16 millionAmericans with AD by the year 2050 [1].Pathologically, AD is characterized by an abundance ofneurof i brillary tangles (NFT), senile plaques (SP), neuropilthread formation, and A𝛽 deposition; neuron and synapseloss; and proliferation of reactive astrocytes, particularly inthe hippocampus, amygdala, entorhinal cortex, and neocor-tex.NFTarecomposedofintracellulardepositsofpairedheli-cal f i laments composed of hyperphosphorylated tau. Senileplaques are present as dif f use plaques composed of amor-phous extracellular deposits of amyloid beta (A𝛽) that lackneuritesandneuriticplaques(NP)composedofextracellulardeposits of insoluble A𝛽 surrounded by dystrophic neurites,reactive astrocytes, and activated microglia. In addition tonsoluble A𝛽 present in SP, soluble A𝛽 oligomers are presentintheADbrainandmayrepresentthemaintoxicformofA𝛽,thus implicating them in the disease process [2–4].Currently, two classes of medications are FDA approvedfor use by AD patients including cholinesterase inhibitors(Aricept) and an N-methyl-D-aspartate (NMDA) antagonist(Memantine). Although these therapeutics show clinicalbenef i t in some patients, many do not respond. Additionally,these drugs do not signif i cantly modify disease progressionand perhaps more importantly are not approved for patientsat earlier stages of the disease (mild cognitive impairment;MCI). For these reasons there is a critical need to identifyadditional therapeutics that can be initiated early in diseaseHindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015, Article ID 787805, 9 pageshttp://dx.doi.org/10.1155/2015/787805