[Abstract Title]. - Society for Neuroscience

Abstract: Aggregation of 42-mer amyloid β (Aβ42) peptide is a key event in the pathology of
Alzheimer‟s disease (AD). Aβ42 aggregates to induce neurotoxicity mainly through the
formation of radicals. Recent research suggested that the isomerization and/or racemization of
Asp residues at position 1, 7, or 23 of Aβ42 might be associated with its pathology. Our previous
study using systematic proline replacement and electron spin resonance (ESR) spectrometry
suggested that turn formation at positions 22 and 23 of Aβ42 could be closely related to the
radical production by the interaction between the side chains of Met35 and Tyr10. 1,2) To
investigate the contribution of the posttranslational modifications (isomerization and/or
racemization) at Asp23 to its pathology, three isomerized and/or racemized Aβ42 mutants (LisoAsp23-,
D-Asp23-, and D-isoAsp23-Aβ42) were examined for its aggregative ability both by
the sedimentation assay using HPLC and the thioflavin-T fluorescence, neurotoxicity in PC12
cells by the MTT assay, and radical productivity by ESR using phenyl-tert-butylnitrone (PBN) as
a trapping reagent. All Aβ42 mutants except for D-isoAsp23-Aβ42 showed moderate
aggregative ability similar to wild-type Aβ42. However, the neurotoxicity of D-Asp23-Aβ42 was
weaker than that of wild-type Aβ42, while that of L-isoAsp23-Aβ42 was as potent as that of
wild-type Aβ42. In contrast, D-isoAsp23-Aβ42 showed weak aggregative ability without
neurotoxicity. Their ability to produce radicals correlated well with their corresponding
neurotoxicity. These results suggest that the isomerization and/or racemization of Asp23 might
not be related to the pathogenesis of AD, but could be a consequence of chemical reaction during
the long-term deposition of amyloid fibrils. If these modifications at Asp23 of Aβ42 were
involved in the pathogenesis of AD, a possibility other than the neurotoxicity of Aβ42 peptides
themselves, such as resistance to the enzymatic degradation, should be considered. 3)
1) Murakami et al., J. Am. Chem. Soc. 2005, 127, 15168-15174
2) Murakami et al., ChemBioChem 2007, 8, 2308-2314
3) Murakami et al., Biochem. Biophys. Res. Commun. 2008, 366, 745-751
Disclosures: K. Murakami , None; T. Shimizu, None; M. Uno, None; Y. Masuda, None; K.
Irie, None; T. Shirasawa, None.
Poster
244. Abeta Toxicity I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 244.25/N6
Topic: C.01.b. Abeta assembly and deposition
Support: A Grant-in-aid for Scientific Research (A) (No.18208011 for K.I.) from the Ministry
of Education, Science, Culture, Sports, and Technology of the Japanese Government