FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines.
One of the pathological hallmarks of Alzheimer's disease is the presence of insoluble extracellular amyloid plaques. These plaques are mainly constituted of amyloid beta peptide (A beta), a proteolytic product of amyloid precursor protein (APP). APP processing also generates the APP intracellular domain (AICD). We have previously demonstrated that AICD interacts with FKBP12, a peptidyl-prolyl cis-trans isomerase (PPIase) ubiquitous in nerve systems. This interaction was interfered by FK506, a clinically used immunosuppressant that has recently been reported to be neuroprotective. To elucidate the roles of FKBP12 in the pathogenesis of Alzheimer's disease, the effect of FKBP12 overexpression on APP processing was evaluated. Our results revealed that APP processing was shifted towards the amyloidogenic pathway, accompanied by a change in the subcellular localization of APP, upon FKBP12 overexpression. This FKBP12-overexpression-induced effect was reverted by FK506. These findings support our hypothesis that FKBP12 may participate in the regulation of APP processing. FKBP12 overexpression may lead to the stabilization of a certain isomer (presumably the cis form) of the Thr668-Pro669 peptide bond in AICD, therefore change its affinity to flotillin-1 or other raft-associated proteins, and eventually change the localization pattern and cause a shift in the proteolytic processing of APP.
School of Pharmacy, National Taiwan University, Taipei 10051, Taiwan, R.O.C.
Fan-Lun
FL
Liu
Ting-Yi
TY
Liu
Fan-Lu
FL
Kung
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology*; D016559:Tacrolimus / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C106354:flotillins; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus