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© The Rockefeller University Press, 0021-9525/2003/10/83 $8.00
The Journal of Cell Biology, Volume 163, Number 1, 83-95

APP processing is regulated by cytoplasmic phosphorylation

¹ Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115
² Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
³ Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478
⁴ Department of CNS Discovery, Pfizer Central Research, Groton, CT 06340

Address correspondence to Li-Huei Tsai, Dept. of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Ave., Boston, MA 02115. Tel.: (617) 432-1053. Fax: (617) 432-3975. email: li-huei_tsai{at}hms.harvard.edu

Amyloid-ß peptide (Aß) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the ß-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by -secretase. The production of Aß is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aß generation.

Key Words: Alzheimer's disease; amyloid precursor protein; BACE1; endosomes; Aß

The online version of this paper contains supplemental material.

Abbreviations used in this paper: Aß, amyloid-ß peptide; AD, Alzheimer's disease; APLP, APP-like protein; APP, amyloid precursor protein; CTF, COOH-terminal fragment; HSV, herpes simplex virus; MS, mass spectrometry; P-APP, APP phosphorylated on threonine 668; PNS, postnuclear supernatant; PS, presenilin.

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