Presentation Title

The Deposition of β -Amyloid Proteins 1-40 & 1-42 in the Myocardium of Alzheimer’s and Type 2 Diabetes

Faculty Mentor

Jonathan J. Wisco

Start Date

23-11-2019 8:00 AM

End Date

23-11-2019 8:45 AM

Location

187

Session

poster 1

Type of Presentation

Poster

Subject Area

health_nutrition_clinical_science

Abstract

The onset of Type 2 Diabetes (TD2) is characterized by cellular insulin resistance and excess blood sugar. T2D has an increased risk of heart disease, which could result in damage to the heart musculature and blood vessels. The protein amyloid beta (Aβ) is known to disrupt normal functioning of the mitochondria, which results in a fatal cascade of events that can lead to the development of Alzheimer’s disease (AD). Due to theAβ aggregation, a neuron’s communication with other cells is disrupted and immune cells to trigger inflammation resulting in death of brain cells. The 40-residue peptide Aβ (1-40) exerts detrimental effects on the cardiovascular system by promoting vascular inflammation, while the 42-residue Aβ (1-42) plays a major role in the formation of fibrils, leading to significant increase of amyloid deposition extra-neuronally. There is limited research which examines the role of how Aβ (1-40) and Aβ (1-42) affect myocardial function in AD patients with T2D. Our previous studies suggested Aβ co-localizes with iron in the brain, which can be measured from MR images. One of the main challenges for patients with AD and T2D is they are more susceptible to develop extra stiffness in the ventricle, making it more difficult to pump blood. The current study consisted of 20 ex vivo AD heart apex biopsies from 20-day old wild-type and two human transgenic (APP/PS1 and TAU) mice. Each heart apex biopsy was harvested and placed in formalin for fixation. We imaged the biopsies with a Bruker 11.7T MRI using the Fast-Low Angle Shot (FLASH), Fast Imaging with Steady-state free Precession (FISP), and Rapid Acquisition with Relaxation Enhancement (RARE) sequences. One image slice of the base of each heart apex was sampled for mean signal intensity within a 2 mm2 region of interest (ROI) drawn in Horos (https://horosproject.org). A second 2 mm2 ROI was measured outside the tissue for each image in order to establish a standard signal intensity. The intra-extra tissue mean signal ratio was used for one-way ANOVA statistical analysis. We anticipated a significant decrease in the signal intensity in the T2 based images, FISP and RARE, denoting the iron-associated pathogenesis of AD and T2D. The statistical model, comparing abeta, tau, and wild type heart FISP signal was not significant (p=0.833), however. Our results may be due to several factors: an insufficient amount of pathological proteins is deposited in the heart wall by 20 days, and therefore no additional iron deposits in the myocardium; or, any additional iron associating with AD pathology is overshadowed by the endogenous iron present in the myocardium. To confirm either of these hypotheses, we will follow-up with histological analysis. In addition, we will perform MRI and histology studies on heart apices from mice at 3, 6, 9, and 12 months when we expect the AD pathology to progress.

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Nov 23rd, 8:00 AM Nov 23rd, 8:45 AM

The Deposition of β -Amyloid Proteins 1-40 & 1-42 in the Myocardium of Alzheimer’s and Type 2 Diabetes

187

The onset of Type 2 Diabetes (TD2) is characterized by cellular insulin resistance and excess blood sugar. T2D has an increased risk of heart disease, which could result in damage to the heart musculature and blood vessels. The protein amyloid beta (Aβ) is known to disrupt normal functioning of the mitochondria, which results in a fatal cascade of events that can lead to the development of Alzheimer’s disease (AD). Due to theAβ aggregation, a neuron’s communication with other cells is disrupted and immune cells to trigger inflammation resulting in death of brain cells. The 40-residue peptide Aβ (1-40) exerts detrimental effects on the cardiovascular system by promoting vascular inflammation, while the 42-residue Aβ (1-42) plays a major role in the formation of fibrils, leading to significant increase of amyloid deposition extra-neuronally. There is limited research which examines the role of how Aβ (1-40) and Aβ (1-42) affect myocardial function in AD patients with T2D. Our previous studies suggested Aβ co-localizes with iron in the brain, which can be measured from MR images. One of the main challenges for patients with AD and T2D is they are more susceptible to develop extra stiffness in the ventricle, making it more difficult to pump blood. The current study consisted of 20 ex vivo AD heart apex biopsies from 20-day old wild-type and two human transgenic (APP/PS1 and TAU) mice. Each heart apex biopsy was harvested and placed in formalin for fixation. We imaged the biopsies with a Bruker 11.7T MRI using the Fast-Low Angle Shot (FLASH), Fast Imaging with Steady-state free Precession (FISP), and Rapid Acquisition with Relaxation Enhancement (RARE) sequences. One image slice of the base of each heart apex was sampled for mean signal intensity within a 2 mm2 region of interest (ROI) drawn in Horos (https://horosproject.org). A second 2 mm2 ROI was measured outside the tissue for each image in order to establish a standard signal intensity. The intra-extra tissue mean signal ratio was used for one-way ANOVA statistical analysis. We anticipated a significant decrease in the signal intensity in the T2 based images, FISP and RARE, denoting the iron-associated pathogenesis of AD and T2D. The statistical model, comparing abeta, tau, and wild type heart FISP signal was not significant (p=0.833), however. Our results may be due to several factors: an insufficient amount of pathological proteins is deposited in the heart wall by 20 days, and therefore no additional iron deposits in the myocardium; or, any additional iron associating with AD pathology is overshadowed by the endogenous iron present in the myocardium. To confirm either of these hypotheses, we will follow-up with histological analysis. In addition, we will perform MRI and histology studies on heart apices from mice at 3, 6, 9, and 12 months when we expect the AD pathology to progress.