The Impact of Islet Amyloid Polypeptide on Brain Pericytes and Autoantibody Levels in Alzheimer's Disease

Popular Abstract

The reason behind brain pericyte death in Alzheimer's disease

Alzheimer's disease (AD) is a widespread neurodegenerative disorder with more than 46 million people living with AD worldwide. The most characteristic clinical symptoms of AD are memory loss and behavioural issues, affecting the daily life of those suffering from AD and their caregivers. Unfortunately, despite extensive research, there are still no FDA-approved drugs that could cure AD.

The clinical symptoms of AD are the result of disease-specific alterations in the brain. For example, an accumulation of protein Aβ is one of the most characteristic changes seen in AD patients. Aβ might accumulate due to genetics (2%) or other risk factors (98%). Understanding how these risk factors enhance the risk for AD can aid future research in preventive care, diagnosis, and treatment. Therefore, in the current study, we analyzed two AD-related factors, APOE ε4 and islet amyloid polypeptide (IAPP). Apoe4 is a protein involved in fat metabolism, and carrying the APOE ε4 gene increases the risk of developing AD up to 2-12 times. IAPP, on the other hand, is a protein involved in glucose metabolism, and it has been shown that Type 2 diabetes patients, who have double the risk for developing AD, have increased levels of both, IAPP and with it associated autoantibodies. IAPP is known to aggregate and accumulate in peripheral organs, where it has a toxic impact on cells. Recently, aggregated IAPP, together with Aβ, was found in brain vessels, and more specifically, in pericytes (Figure 1). Pericytes are cells known to stabilize small vessels and maintain the blood-brain barrier, which protects the brain from harmful molecules and bacteria from the periphery. In what way IAPP affects pericytes is scarcely known. Therefore, we stimulated brain pericytes with aggregated IAPP and analyzed alterations in pericyte viability and protein secretion. We found that once IAPP is taken up by pericytes (approximately after 3 hours), it increases the production of several proteins necessary for pericyte survival, indicating that IAPP has a strong impact on pericyte function. To further investigate how IAPP is related to AD-associated changes in a clinical and APOE ε4 context, we measured IAPP-autoantibody levels in plasma samples from AD patients and healthy age-matched individuals. Although we found no differences in IAPP-autoantibody levels between AD patients and healthy individuals, we noted that individuals carrying the APOE ε4 gene had much lower levels of an autoantibody isotype called IgA. These results indicate that the APOE ε4 allele affects IgA IAPP-autoantibody turnover or clearance of IAPP. In conclusion, we suggest that IAPP affects pericyte viability and functions and that clearance via autoantibodies is altered in APOE ε4 carriers, supporting a role for IAPP in AD. Thus, we hope that findings of this study will contribute towards understanding how to treat AD.





Master’s Degree Project in Molecular Biology 60 credits 2021
Department of Biology, Lund University

Advisor: Malin Wennström
Advisors Unit/Department (or Company or Authority): Clinical Memory Research Unit, Department of Clinical Sciences, Lund University

• author: Poceviciute, Dovile
• supervisor: Malin Wennström
• organization: Degree Projects in Molecular Biology
• course: MOBN03 20202
• year: 2021
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 9055308
• date added to LUP: 2021-06-16 11:57:13
• date last changed: 2021-06-16 11:57:13