We reviewed here that
protein isomerization is enhanced in
amyloid-beta peptides (Abeta) and paired helical filaments (PHFs) purified from
Alzheimer's disease (AD) brains. Biochemical analyses revealed that Abeta purified from
senile plaques and vascular
amyloid are isomerized at Asp-1 and Asp-7. A specific antibody recognizing isoAsp-23 of Abeta further suggested the isomerization of Abeta at Asp-23 in vascular
amyloid as well as in the core of
senile plaques. Biochemical analyses of purified PHFs also revealed that heterogeneous molecular weight tau contains L-
isoaspartate at Asp-193, Asn-381, and Asp-387, indicating a modification, other than phosphorylation, that differentiates between normal tau and PHF tau. Since
protein isomerization as L-
isoaspartate causes structural changes and functional inactivation, or enhances the aggregation process, this modification is proposed as one of the progression factors in AD.
Protein L-isoaspartyl methyltransferase (PIMT) is suggested to play a role in the repair of isomerized
proteins containing L-
isoaspartate. We show here that PIMT is upregulated in neurodegenerative neurons and colocalizes in neurofibrillary tangles (NFTs) in AD. Taken together with the enhanced
protein isomerization in AD brains, it is implicated that the upregulated PIMT may associate with increased
protein isomerization in AD. We also reviewed studies on PIMT-deficient mice that confirmed that PIMT plays a physiological role in the repair of isomerized
proteins containing L-
isoaspartate. The knockout study also suggested that the brain of PIMT-deficient mice manifested neurodegenerative changes concomitant with accumulation of L-
isoaspartate. We discuss the pathological implications of
protein isomerization in the neurodegeneration found in model mice and AD.