Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease

Kazuhiro Nakamura, Alex Greenwood, Lester Binder, Eileen H. Bigio, Sarah Denial, Linda Nicholson, Xiao Zhen Zhou*, Kun Ping Lu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

cis-trans isomerization of proteins phosphorylated by proline-directed kinases is proposed to control numerous signaling molecules and is implicated in the pathogenesis of Alzheimer's and other diseases. However, there is no direct evidence for the existence of cis-trans protein isomers in vivo or for their conformation-specific function or regulation. Here we develop peptide chemistries that allow the generation of cis- and trans-specific antibodies and use them to raise antibodies specific for isomers of phosphorylated tau. cis, but not trans, p-tau appears early in the brains of humans with mild cognitive impairment, accumulates exclusively in degenerated neurons, and localizes to dystrophic neurites during Alzheimer's progression. Unlike trans p-tau, the cis isomer cannot promote microtubule assembly, is more resistant to dephosphorylation and degradation, and is more prone to aggregation. Pin1 converts cis to trans p-tau to prevent Alzheimer's tau pathology. Isomer-specific antibodies and vaccines may therefore have value for the early diagnosis and treatment of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)232-244
Number of pages13
JournalCell
Volume149
Issue number1
DOIs
StatePublished - Mar 30 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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