Sortilin-related Receptor with A-type Repeats (SORLA) Affects the Amyloid Precursor Protein-dependent Stimulation of ERK Signaling and Adult Neurogenesis

Gerd Kempermann,Olav M. Andersen,Anne-Sophie Carlo,Christian Wozny,Thomas E. Willnow,Thomas A. Bayer,Michael Rohe,Henning Breyhan,Steven M. Paul,Bettina Erdmann,Anja Harmeier,Vanessa Schmidt,Daniel Militz,Anje Sporbert,Kelly R. Bales,Dietmar Schmitz,Susanne Wolf

doi:10.1074/jbc.m710574200

Abstract

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.

Highlights

14826 JOURNAL OF BIOLOGICAL CHEMISTRY receptor promotes retention of amyloid precursor protein (APP) in subcellular compartments less favorable for processing and thereby reduces the extent of proteolytic breakdown into both amyloidogenic and non-amyloidogenic products
Loss of receptor activity was shown to increase the overall production of sAPP and A␤, in line with an inverse correlation of receptor activity and APP processing rates in cultured cells [3]
In hippocampal neurons from newborn mice detail the consequences of the loss of Sortilin-related receptor with A-type repeats (SORLA) activity in vivo, doubly transgenic for human AppV717F and the Sorla null allele, focusing on the hippocampus, a region in the brain levels of full-length human APP were reduced (Fig. 3A) but that is especially vulnerable to Alzheimer disease (AD)-related disease processes. concentrations of human sAPP␣ (Fig. 3, A and B), sAPP␤

Summary

Introduction

14826 JOURNAL OF BIOLOGICAL CHEMISTRY receptor promotes retention of APP in subcellular compartments less favorable for processing and thereby reduces the extent of proteolytic breakdown into both amyloidogenic and non-amyloidogenic products. Consistent with its protective role in APP catabolism, increasing SORLA expression in cells reduces conversion of APP to the amyloid ␤-peptide (A␤) and soluble (s) APP fragments, while low levels of receptor activity accelerate generation of these processing products [3, 4, 6].

Results

Conclusion