Abstract
ObjectivesAmple 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 Ca2+ 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.MethodsCardiomyocyte 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 Ca2+ transient rise and decay.ResultsLittle 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 Ca2+ was lower accompanied by unchanged resting/peak intracellular Ca2+ levels and intracellular Ca2+ 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 β1-adrenergic receptor expression was unchanged in APP/PS1 hearts. Expression of the Ca2+ regulatory protein phospholamban and protein carbonyl formation were downregulated and elevated, respectively, associated with unchanged SERCA2a, Na+-Ca2+ 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.ConclusionsOur results depicted overt cardiomyocyte mechanical dysfunction in the APP/PS1 Alzheimer's disease model, possibly due to oxidative stress.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to memory loss and cognitive impairment
APPswe/ PS1dE9 mice were developed by co-injection of the two transgene constructs [mouse/human (Mo/Hu) chimeric APP695 harboring the Swedish (K594M/N595L) mutation and exon-9-deleted presenilin 1 (PS1)] into pronuclei with a single genomic insertion site resulting in the two transgenes being transmitted as a single mendelian locus
General features of animals and ECG analysis Little difference was identified in tibial length, body and organ weights between the APPswe/PS1dE9 transgenic (APP/PS1) mice and their wild-type (WT) littermates
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to memory loss and cognitive impairment. Accumulation of amyloid b-peptide (Ab) and neurofibrillary tangles are considered hallmarks for neuropathological changes in AD. At this time, neither the precise pathogenesis nor radical cure is available for AD. AD is associated with a high prevalence of heart dysfunction in the elderly. Recent data has indicated a close tie between heart dysfunction and AD. Given that the AD genes PS1 and PS2 are expressed in the heart [11], it may be speculated that mutations in these genes in familial AD affect cardiac function. Presenilins have been suggested to play a key role in the regulation of cardiovascular function. PS1 and PS2 mutations are associated with a higher risk of dilated cardiomyopathy and heart failure in AD patients [14]
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