Isomerization of
L-aspartate and deamidation of
L-asparagine in
proteins or
peptides dominantly give rise to L-
isoaspartate by a non-enzymatic reaction via
succinimide as a intermediate under physiological conditions. Isoaspartates have been identified in a variety of cellular
proteins in vivo as well as pathologically deposited
proteins in neurodegenerative brain tissue. We described here that the formation of
isoaspartate is enhanced in
amyloid-beta (Abeta)
peptides in
Alzheimer's disease (AD). Specific
antibodies recognizing
isoaspartate of Abeta revealed that isomerized Abeta
peptides were deposited in
senile plaques as well as
amyloid-bearing vessels. Moreover, it was revealed that Abeta
peptides, isomerized at position 7 or 23, were differentially deposited in
senile plaques and vascular amyloids in AD brains. In vitro experiments showed that the modification at position 23 greatly enhanced the aggregation of Abeta. Furthermore, systematic
proline substitution analyses revealed that the beta-turn structure at positions 22 and 23 of Abeta42 plays a crucial role in the aggregation and neurotoxicity of Abeta
peptides. It is suggested that spontaneous isomerization at position 23 induces the conformational change to form a beta-turn at position 23, which plays a pathogenic role in the deposition of Abeta
peptides in sporadic AD.
Protein L-isoaspartyl methyltransferase (PIMT) is a putative
protein repair
enzyme, which converts L-isoaspartyl residues in damaged
proteins to normal L-aspartyl residues. PIMT-deficient mice manifested neurodegenerative changes concomitant with the accumulation of L-
isoaspartate in the brain. We discuss here the pathological implications of the formation of
isoaspartate in damaged
proteins during neurodegeneration in model mice and AD.