Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis.
Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid beta-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with pro-found stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.
Rohe
Michael
M
Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
Carlo
Anne-Sophie
AS
Breyhan
Henning
H
Sporbert
Anje
A
Militz
Daniel
D
Schmidt
Vanessa
V
Wozny
Christian
C
Harmeier
Anja
A
Erdmann
Bettina
B
Bales
Kelly R
KR
Wolf
Susanne
S
Kempermann
Gerd
G
Paul
Steven M
SM
Schmitz
Dietmar
D
Bayer
Thomas A
TA
Willnow
Thomas E
TE
Andersen
Olav M
OM
D000375:Aging / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D004594:Electrophysiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases