Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis

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

Research output: Contribution to journalArticle

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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.
LanguageEnglish
Pages14826-14834
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number21
Early online date24 Mar 2008
DOIs
Publication statusPublished - 23 May 2008

Fingerprint

Amyloid beta-Protein Precursor
Neurogenesis
Alzheimer Disease
Amyloid beta-Peptides
Processing
Sorting
Metabolism
Neurons
sortilin
Brain
Anatomy
Genes
Defects

Keywords

  • aging
  • Amyloid beta-Protein Precursor
  • animals
  • cell differentiation
  • electrophysiology
  • enzyme activation
  • extracellular signal-regulated MAP kinases
  • MAP kinase signaling system
  • membrane transport proteins
  • mice
  • mice, knockout
  • neurons
  • patch-clamp techniques
  • receptors, LDL

Cite this

Rohe, Michael ; Carlo, Anne-Sophie ; Breyhan, Henning ; Sporbert, Anje ; Militz, Daniel ; Schmidt, Vanessa ; Wozny, Christian ; Harmeier, Anja ; Erdmann, Bettina ; Bales, Kelly R. ; Wolf, Susanne ; Kempermann, Gerd ; Paul, Steven M. ; Schmitz, Dietmar ; Bayer, Thomas A. ; Willnow, Thomas E. ; Andersen, Olav M. / Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 21. pp. 14826-14834.
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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.",
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author = "Michael Rohe and Anne-Sophie Carlo and Henning Breyhan and Anje Sporbert and Daniel Militz and Vanessa Schmidt and Christian Wozny and Anja Harmeier and Bettina Erdmann and Bales, {Kelly R.} and Susanne Wolf and Gerd Kempermann and Paul, {Steven M.} and Dietmar Schmitz and Bayer, {Thomas A.} and Willnow, {Thomas E.} and Andersen, {Olav M.}",
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Rohe, M, Carlo, A-S, Breyhan, H, Sporbert, A, Militz, D, Schmidt, V, Wozny, C, Harmeier, A, Erdmann, B, Bales, KR, Wolf, S, Kempermann, G, Paul, SM, Schmitz, D, Bayer, TA, Willnow, TE & Andersen, OM 2008, 'Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis' Journal of Biological Chemistry, vol. 283, no. 21, pp. 14826-14834. https://doi.org/10.1074/jbc.M710574200

Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. / Rohe, Michael; Carlo, Anne-Sophie; Breyhan, Henning; Sporbert, Anje; Militz, Daniel; Schmidt, Vanessa; Wozny, Christian; Harmeier, Anja; Erdmann, Bettina; Bales, Kelly R.; Wolf, Susanne; Kempermann, Gerd; Paul, Steven M.; Schmitz, Dietmar; Bayer, Thomas A.; Willnow, Thomas E.; Andersen, Olav M.

In: Journal of Biological Chemistry, Vol. 283, No. 21, 23.05.2008, p. 14826-14834.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis

AU - Rohe, Michael

AU - Carlo, Anne-Sophie

AU - Breyhan, Henning

AU - Sporbert, Anje

AU - Militz, Daniel

AU - Schmidt, Vanessa

AU - Wozny, Christian

AU - Harmeier, Anja

AU - Erdmann, Bettina

AU - Bales, Kelly R.

AU - Wolf, Susanne

AU - Kempermann, Gerd

AU - Paul, Steven M.

AU - Schmitz, Dietmar

AU - Bayer, Thomas A.

AU - Willnow, Thomas E.

AU - Andersen, Olav M.

PY - 2008/5/23

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N2 - 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.

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KW - aging

KW - Amyloid beta-Protein Precursor

KW - animals

KW - cell differentiation

KW - electrophysiology

KW - enzyme activation

KW - extracellular signal-regulated MAP kinases

KW - MAP kinase signaling system

KW - membrane transport proteins

KW - mice

KW - mice, knockout

KW - neurons

KW - patch-clamp techniques

KW - receptors, LDL

U2 - 10.1074/jbc.M710574200

DO - 10.1074/jbc.M710574200

M3 - Article

VL - 283

SP - 14826

EP - 14834

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T2 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

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