title: Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease.
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.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Alex
authors.initials: A
authors.lastname: Greenwood
authors.forename: Lester
authors.initials: L
authors.lastname: Binder
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Sarah
authors.initials: S
authors.lastname: Denial
authors.forename: Linda
authors.initials: L
authors.lastname: Nicholson
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007536:Isomerism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D011392:Proline / Q000737:chemistry* / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; D011392:Proline; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse