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Cardiomyocyte contractile dysfunction in the APPswe/PS1dE9 mouse model of Alzheimer's disease
Subat Turdi1, Rui Guo, Anna F Huff
1Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
Insights
Alzheimer
Area of Science:
- Cardiovascular Research
- Neuroscience
- Cellular Biology
Background:
- Alzheimer's disease (AD) is linked to increased cardiovascular events.
- Investigating cardiac function in AD models is crucial for understanding disease comorbidities.
Purpose of the Study:
- To investigate myocardial histology, cardiomyocyte function, and intracellular calcium (Ca2+) handling in the APPswe/PS1dE9 (APP/PS1) mouse model of AD.
- To assess adrenergic response, endoplasmic reticulum (ER) stress, and oxidative stress markers in the hearts of APP/PS1 mice.
Main Methods:
- Evaluated cardiomyocyte mechanical properties (peak shortening, velocity of shortening/relengthening) and intracellular Ca2+ transients.
- Assessed myocardial histology, gene/protein expression (adrenergic receptors, phospholamban, SERCA2a), and protein carbonyl formation.
- Administered N-acetylcysteine as an antioxidant intervention.
Main Results:
- APP/PS1 mice exhibited cardiomyocyte contractile dysfunction, including depressed peak shortening and reduced maximal velocity of shortening/relengthening.
- Intracellular Ca2+ transient rise was diminished in APP/PS1 cardiomyocytes, with altered responsiveness to adrenergic stimulation.
- Elevated protein carbonyl formation (oxidative stress) and downregulated phospholamban were observed; antioxidant treatment attenuated dysfunction.
Conclusions:
- The APP/PS1 Alzheimer's disease model displays significant cardiomyocyte mechanical dysfunction.
- Oxidative stress is implicated as a potential contributor to the observed cardiac dysfunction in this AD model.
Objectives:
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.
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