Amyloid Aggregation in Alzheimer’s and Parkinson’s Diseases

Abstract (Swedish)

Many evidence supports the notion that protein aggregation in the brain leads to neurodegenerative diseases, characterized by progressive degeneration of neuron structure and function in the brain. Protein aggregation causes a variety of diseases such Alzheimer’s disease (AD) and Parkinson’s disease (PD). Generation of extracellular amyloid-beta (Ab) plaques and aggregation of α-synuclein (α-syn), are the hallmarks of AD. This project aims to study co-aggregation of Ab and α-syn in the brain of a newly generated double transgenic mouse model of AD. With the use of amyloid dyes, I confirmed the presence of both Ab and α-syn aggregation in the brain tissue of 7-month old mice, thus this model can be used to address the big question “the co-localization of α-syn in Ab plaques”. Most importantly, I demonstrated an overlap of aggregated Ab and α-syn within amyloid plaques. I found a high degree of co-localization of a-syn oligomers with Ab plaques which can indicate the interaction of Ab and α-syn. Thus, the model can be used to address an important question: the role of α-syn in amyloid-beta aggregation.

Popular Abstract

Several studies suggest that protein aggregation in the brain leads to neurodegenera-tive diseases. Two examples of this are seen in the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD) in the form of a-synuclein (a-syn) and amyloid-beta (Ab) plaques, respectively. However, an overlap of these pa-thologies has been observed in more than 50% of AD cases. This research focuses on the pathological and clinical correlation between AD and PD, which is achieved through studying the co-aggregation of Ab and a-syn in a mouse whose brain contains the genes of both diseases (a double transgenic mouse model).

The most common cause of dementia is AD, which accounts for up to 80 % of dementia diagnoses. Two major features that often present as indicators of AD progression are known as plaques and tangles, both of which are types of protein aggregation. Plaques contain Ab inclusions, which are produced by amyloid precursor protein (APP), while tangles consist of a specific protein called tau. The presence of intracellular soluble Ab leads to the abnormal phosphorylation of tau.

The second most frequent progressive neurodegenerative disease is PD, with ten million people affected worldwide. Many researchers have noted changes in the brain of people affected with PD, such as the presence of Lewy bodies, another type of protein aggregation, that contain a-syn along with hyperphos-phorylated tau. Patients with PD have a fourfold higher chance of developing dementia compared to the general population, while 50 % develop cognitive problems and dementia 10 years after diagnosis.

Misfolding of a protein can lead to its aggregation, involving a process in which monomers (individual units) interact, forming larger and larger complexes and eventually becoming insoluble fibrillar deposits that can be seen under the microscope as plaques. Many studies provide the necessary arguments that soluble nonfibrillar forms of Ab and a-syn are neurotoxins.

The discovery of the preventive mutation in the APP gene against sporadic AD has proved the Ab hypothesis that was originally established on the discovery of a gene mutation that cause familial AD. The Ab hypothesis states that several kinds of mutation within the APP gene favor Ab to aggregate. This hypothesis has favored the utilization of transgenic mouse models with an overproduction of APP in studies of AD with an experimental approach.

In this research, brain tissues of the double transgenic mouse model were used to study the co-localization of a-syn with Ab amyloid plaques, and the structure content in amyloid plaques. Immunofluores-cence was performed using antibodies targeting Ab and a-syn. A high co-localization of a-syn with Ab was observed in amyloid plaques that consisted of oligomers structure, which are believed to be the toxic species in Ab plaques. Focusing on the co-existence of disease-related proteins and their pathogenic structure can be an effective therapeutic approach for dementia diseases.

Master’s Degree Project in Biology/Molecular Biology/Bioinformatics 30 credits 2020 Department of Biology, Lund University
Advisor: Oxana Klementieva.
Medical Microspectroscopy research group/Lund University/Sweden

• author: Hady, Flora
• supervisor: Oxana Klementieva
• organization: Degree Projects in Molecular Biology
• course: MOBY10 20201
• year: 2020
• type: H1 - Master's Degree (One Year)
• subject: Biology and Life Sciences
• language: English
• id: 9029192
• date added to LUP: 2020-09-14 12:30:20
• date last changed: 2020-09-14 12:30:20