APP intracellular domain-WAVE1 pathway reduces amyloid-β production.
An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD), but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Ilaria
I
Ceglia
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.|The Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.|Department of Neurology, Columbia University, New York, New York, USA.|Department of Epidemiology, Columbia University, New York, New York, USA.
Christiane
C
Reitz
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Jodi
J
Gresack
Department of Biochemistry, Ewha Womans University, Seoul, South Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, South Korea.
Jung-Hyuck
JH
Ahn
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Victor
V
Bustos
Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York, USA.
Marina
M
Bleck
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Xiaozhu
X
Zhang
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Grant
G
Martin
Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York, USA.
Sanford M
SM
Simon
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.|Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Angus C
AC
Nairn
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Paul
P
Greengard
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
Yong
Y
Kim
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051300:Wiskott-Aldrich Syndrome Protein Family