N, Aarthi
(2016)
Study on the effect of Stress conditions on Alzheimer’s disease using yeast Aβ42-MRF oligomerisation model.
Masters thesis, Indian Institute of Technology Hyderabad.
Abstract
Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized
by an extracellular deposition of amyloid plaques, and an intraneuronal
accumulation of neurofibrillary tangles in the brain of affected individuals. A
42 amino acid long Aβ42 peptide generated by proteolytic processing of the
APP protein is a major component of the amyloid plaques, in which it is
mainly represented in the form of detergent-insoluble amyloid fibers.
Previously, the Aβ42 fibers have been considered to be the major pathogenic
agents of AD. Thus Small molecules that prevent the formation of Aβ42
aggregates that lead to the formation of large plaques had previously been of
interest. Recently, this hypothesis has been challenged by findings suggesting
that fibrillar aggregates may represent inert dead-end products of the Aβ42
aggregation pathway. Considerable evidence now suggests that the primary
neurotoxic effects are associated with soluble SDS-stable assemblies of Aβ42,
such as 56 kDa Aβ42 dodecamers, or even smaller, low-n (dimers, trimers, and
tetramers) oligomers of Aβ42, which seem to appear during the early stages of
Aβ42 assembly, and could give rise to larger oligomers. Thus, the focus of
putative therapeutic interventions have shifted towards unravelling
compounds that inhibit the earliest stages of Aβ42 oligomerization.
In yet another finding, the frequency of [PSI +] induction, the prion of Sup35
(Yeast Translation Termination Factor) increased with stress. This stress
related prion induction can be extrapolated to AD using Aβ42-MRF
oligomerisation model that mimics [PSI +].
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