Cardiomyocyte contractile dysfunction in the APPswe/PS1dE9 mouse model of Alzheimer's disease.
OBJECTIVE
Ample clinical and experimental evidence indicated that patients with Alzheimer's disease display a high incidence of cardiovascular events. This study was designed to examine myocardial histology, cardiomyocyte shortening, intracellular Ca(2+) homeostasis and regulatory proteins, electrocardiogram, adrenergic response, endoplasmic reticulum (ER) stress and protein carbonyl formation in C57 wild-type (WT) mice and an APPswe/PS1dE9 transgenic (APP/PS1) model for Alzheimer's disease.


METHODS
Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR), maximal velocity of shortening and relengthening (+/-dL/dt), intracellular Ca(2+) transient rise and decay.


RESULTS
Little histological changes were observed in APP/PS1 myocardium. Cardiomyocytes from APP/PS1 but not APP or PS1 single mutation mice exhibited depressed PS, reduced+/-dL/dt, normal TPS and TR compared with WT mice(.) Rise in intracellular Ca(2+) was lower accompanied by unchanged resting/peak intracellular Ca(2+) levels and intracellular Ca(2+) decay in APP/PS1 mice. Cardiomyocytes from APP/PS1 mice exhibited a steeper decline in PS at high frequencies. The responsiveness to adrenergic agonists was dampened although beta(1)-adrenergic receptor expression was unchanged in APP/PS1 hearts. Expression of the Ca(2+) regulatory protein phospholamban and protein carbonyl formation were downregulated and elevated, respectively, associated with unchanged SERCA2a, Na(+)-Ca(2+) exchanger and ER stress markers in APP/PS1 hearts. Our further study revealed that antioxidant N-acetylcysteine attenuated the contractile dysfunction in APP/PS1 mice.


CONCLUSIONS
Our results depicted overt cardiomyocyte mechanical dysfunction in the APP/PS1 Alzheimer's disease model, possibly due to oxidative stress.
Turdi
Subat
S
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
Guo
Rui
R
Huff
Anna F
AF
Wolf
Eliza M
EM
Culver
Bruce
B
Ren
Jun
J
D000544:Alzheimer Disease / Q000235:genetics* / Q000628:therapy*; D000682:Amyloid / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009135:Muscular Diseases / Q000235:genetics
D000682:Amyloid; D002118:Calcium