Alzheimer’s of the Heart?
Human heart failure is the leading cause of death in the developed world and represents a final common endpoint for several disease entities, including hypertension, coronary artery disease and the cardiomyopathies.
The lack of pathogenic commonality is underscored by the large number of mutations in different classes of cardiac proteins. The laboratory gathered and published data that not only shows a toxic commonality for various classes of human heart disease but establishes a mechanistic link for heart failure with the neurodegenerative diseases as well.
We showed, first in a genetically engineered mouse, that a dilated cardiomyopathy is characterized by the presence of protein aggregates that are indistinguishable from aggresomes, which are found in a wide variety of human neurodegenerative diseases such as Alzheimer’s and Parkinson’s. We then showed that the aggresomes present in the diseased hearts contain an amyloid oligomer, which may represent the primary toxic species in Alzheimer’s and other neurodegenerative diseases.
Finally, we connected the animal models to human disease by showing that these soluble amyloids are present in a wide variety of human dilated and hypertrophic cardiomyopathies and that they are associated with the contractile apparatus. The data established a new way of thinking about the pathogenic processes that underlie cardiovascular disease and link them to some well-defined neurodegenerative processes. These amyloid oligomers appear in both adult and pediatric heart disease, pointing to the importance of correct protein folding for normal heart function.
We have extended this work in an attempt to find therapeutic interventions. One potential pathway involves the process of autophagy, which the cell uses to recycle its internal components. We have now prepared mice in which we can control this process in the whole animal and are attempting to define the role of this process in potentially clearing the cardiomyocyte of the toxic amyloid oligomer and associated protein aggregates.