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FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines

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Abstract

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 (Aβ), 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.

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Acknowledgements

We thank J-C Wung for the construction of yT&A-APP, T-H Hsieh for the construction of pcDNA3.1(+)APPT668V and pcDNA3.1(+)APPT668E. The authors declare no conflict of interest. This work was supported by funds from the National Science Council of Taiwan (Grant No. NSC-99-2320-B-002-016-MY3) (FLK) and NTU Frontier and Innovative Research Program (Grant No. 97R0334) (FLK).

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Authors and Affiliations

  1. School of Pharmacy, National Taiwan University, Taipei, 10051, Taiwan, R.O.C.

    Fan-Lun Liu, Ting-Yi Liu & Fan-Lu Kung

  2. Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, 10051, Taiwan, R.O.C.

    Fan-Lu Kung

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  1. Fan-Lun Liu
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Correspondence to Fan-Lu Kung.

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Corresponding editors: RAPHAEL PINAUD and DURGADAS P KASBEKAR

MS received 06 November 2012; accepted 24 October 2013

Corresponding editor: Raphael Pinaud and Durgadas P Kasbekar

[Liu F-L, Liu T-Y and Kung F-L 2014 FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines. J. Biosci. 39 1–11] DOI 10.1007/s12038-013-9400-1

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Liu, FL., Liu, TY. & Kung, FL. FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines. J Biosci 39, 85–95 (2014). https://doi.org/10.1007/s12038-013-9400-1

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