(230a) Role of Structure and Stability of β-Amyloid Oligomers and Fibrils On Intracellular Pathways Associated with Alzheimer's Disease

The
detection of β-amyloid (Aβ), a 39 to 43 amino acid peptide, in the
plaques of the human brain is one of the hallmarks of the Alzheimer's disease. While
there is no consensus on the mechanism by which Aβ causes neuron death,
most researchers believe that Aβ is toxic when aggregated and the most
toxic species are certain oligomers formed along the aggregation pathway from
monomer to fibril¹. While there is some evidence that oligomers have
different molecular structure than fibrils², solid state NMR studies
reveal that oligomers have similar molecular structure as fibrils³.

We
believe that along with the molecular structure, the stability of the
aggregates is an important factor that may contribute to the differences in
toxicity of different Aβ aggregate species. It is interesting to observe
that among the two prevalent Aβ peptide isoforms, Aβ(1-42) is more
toxic compared to Aβ(1-40)⁴. In the present study, we prepared
oligomers and fibrils of both Aβ(1-40) and Aβ(1-42), the two most
prevalent Aβ peptides associated with Alzheimer's disease. We confirmed
the structures of both the oligomers and the fibrils using transmission
electron microscopy. We used circular Dichroism to monitor changes in the
secondary structure of both fibrils and oligomers of Aβ(1-40) and
Aβ(1-42) as a function of guanidine hydrochloride concentration. We fit
the data to two and three state unfolding models and estimated free energies of
unfolding for all species. Our results indicate that while both fibrils and
oligomers were rich in β-sheet structure, oligomers were less stable
compared to fibrils. Our results also provide an explanation for the higher
toxicity of aggregates of Aβ(1-42) compared to that of 
Aβ(1-40).

We then examined how
both oligomers and fibrils affect intracellular signaling pathways, focusing
particularly on the ubiquitin proteasome pathway. We are in the process of
using a combination of immunoprecipitation and proteomic techniques to identify
proteins that are uniquely targeted for degradation by the ubiquitin proteasome
pathway. We hypothesize that the targeted proteins may be associated with
neurotransmission which might provide insights into loss of learning and memory
in Alzheimer's disease.

References:

1. Lambert
et al., (1998) Proc.
Natl. Acad. Sci.U. S. A. 95,
6448?6453

2. Kayed,
R et al. (2003) Science 300, 486?489

3.
Chimon S et al., (2007) Nature Struc. and Mol. Bio. 14, 1157-1164

4.
Omar et al., (2000) Biochem. and Biophy. Res. Comm. 273, 1003?1007