Amyloid beta-protein

Protein aggregation, oligomer and fibril formation is one of the dominant
characteristics in the pathogenesis of a number of neurodegenerative diseases, such as
Alzheimer’s disease (AD). Inhibition of toxic oligomer and fibril formation is one of
the approaches to find potential drug candidates for AD. Additionally, early diagnosis
of these amyloid species can provide mechanistic understanding of protein aggregation
and thus can pave the way for preventing the onset of AD. The aim of this dissertation
was 1) to explore the effects of charged cholesterol derivatives on the aggregation
kinetic behavior of Amyloid-β40 (Aβ40), 2) to probe Aβ40 oligomer and amyloid
formation in vitro using gold nanoparticles (AuNPs), and 3) to monitor the kinetic
effect of various natural product molecules on Aβ40 aggregation in vitro. In the first
chapter, a general introduction about AD as an amyloidogenic disease, amyloid cascade
hypothesis, and the manipulation of Aβ peptides aggregation kinetics using different
approaches was presented. In the second chapter, we studied the effects of oppositely charged cholesterol derivatives on the aggregation kinetics of Aβ. In the third chapter,
we developed a gold nanoparticles (AuNPs) assay to probe Aβ40 oligomers and
amyloid formation. In chapter IV, we monitored the effects of various small molecules
on the aggregation kinetics of Aβ40. In chapter V, we discussed the methods and
experimental details.

Alzheimer’s disease (AD) has been defined as a type of dementia that causes
problems with memory, thinking, and behavior. AD is characterized by tau tangles and
Aβ plaques in and around neurons, respectively. The impact this disease has on its
victims’ health, both physically and mentally, is unimaginable and the rate of progression
is not expected to decrease any time soon. This threat to our minds encourages the
importance of understanding AD. Amongst the theories as to what bio mechanisms cause
the brain to intertwine is the amyloid cascade hypothesis. The purpose of this thesis is to
review the amyloid cascade hypothesis and discuss treatments which utilize this model.
We also wish to examine social aspects such as loneliness and socioeconomic factors
which are associated with the progression of AD. Research presented provides evidence
that targeting the accumulation of Aβ in the brain will prevent further biochemical
responses to form neurodegenerative pathology. From the collected data, we observe that
therapies targeting the amyloidogenic pathway have received positive feedback in the
medical community. Amongst them, an Aβ synthetic peptide vaccine which made history
in vaccine development due to their responder rate. The impact of social factors such as
loneliness in the advancement of AD is also supported by research. While it is
acknowledged that any neurodegenerative disease is far too complex to narrow its cause
specifically, this thesis provides an association with multiple aspects that can be
understood and applied to future research in this field.

The pathology of Alzheimer's disease (AD) remains elusive. Competing evidence links amylois \U+fffd\-peptide (A\U+fffd\) amyloid formation to the phenotype of AD (1). The mechanism of amyloid fibril formation has been an ongoing investigation for many years. A\U+fffd\10-23 peptide, a fragment of A\U+fffd\1-42 peptide, contained crucial hydrophobic core residues (2). In this study, an investigation was launched to study the aggreagation process of A\U+fffd\1023 peptide and its ability to form amyloid fibrils. Furthermore, the presence of its hydrophobic core showed importance for its ability to aggregate and form amyloid fibrils. Thereafter, the inhibition of A\U+fffd\1-42 peptide aggregation was studied by using pyrimidine-based compounds. A\U+fffd\1-42 peptides, known to be neurotoxic, aggregate to form amyloid fibrils (3). This investigation may provide insight into the development of novel small molecular candidates to treat AD.