Investigation into the molecular complexity of Alzheimer's disease: an amyloid-ß centered approach

Of all the diseases that lead to dementia, Alzheimer's disease (AD) is the most common, affecting millions of elderly people worldwide. Although a lot of research has been carried out to understand the cellular and molecular events responsible for brain dysfunction and AD pathogenesis, no effective therapy has been identified yet. In the research described in this doctoral thesis we tried to obtain a more detailed understanding of four early hallmarks of AD: Amyloid-beta (Aβ) aggregation, Aβ accumulation, oxidative stress and neuroinflammation.
The thesis starts with an overview on A and its role in Alzheimer’s disease (Chapter 1). Four main sections follow the introduction. The first section consists of a description of chemical compounds designed to inhibit A aggregation and toxicity (Chapter 2 and 3). The second section consists of Chapter 4, which investigates the ability of IDE to cleave different A aggregation species.
Next, the third section reviews the role of oxidative stress in AD and the drugs, currently under clinical trials, aiming at relieving this condition in patients (Chapter 5).
In the last section, the potential link between neuroinflammation and neurodegeneration in AD is explored. In this context, Chapter 6 investigates the microglial IL1-β secretion and loss of neuronal synchronous activity upon exposure to A and interferon gamma (IFN) while Chapter 7 describes the biophysical interaction between A and IFN.
Last, the closing section (chapter 8) consists of concluding remarks and gives some perspectives on promising AD research avenues for the future.
Summarizing, we have aimed at gaining better insights into the molecular complexity of AD. This thesis highlights the multifactorial and complex character of AD and suggests that a multi-target approach, most likely, will contribute to the development of an effective AD therapy, halting the progression of this devastating disease.