Sortilin and SorLA Display Distinct Roles in Processing and Trafficking of Amyloid Precursor Protein

The development and progression of Alzheimer's disease is linked to excessive production of toxic amyloid-β peptide, initiated by β-secretase cleavage of the amyloid precursor protein (APP). In contrast, soluble APPα (sAPPα) generated by the α-secretase is known to stimulate dendritic branching and enhance synaptic function. Regulation of APP processing, and the shift from neurotrophic to neurotoxic APP metabolism remains poorly understood, but the cellular localization of APP and its interaction with various receptors is considered important. We here identify sortilin as a novel APP interaction partner. Like the related APP receptor SorLA, sortilin is highly expressed in the CNS, but whereas SorLA mainly colocalizes with APP in the soma, sortilin interacts with APP in neurites. The presence of sortilin promotes α-secretase cleavage of APP, unlike SorLA, which inhibits the generation of all soluble products. Also, sortilin and SorLA both bind and mediate internalization of sAPP but to different cellular compartments. The interaction involves the 6A domain of APP, present in both neuronal and non-neuronal APP isoforms. This is important as sAPP receptors described so far only bind the non-neuronal isoforms, leaving SorLA and sortilin as the only receptors for sAPP generated by neurons. Together, our findings establish sortilin, as a novel APP interaction partner that influences both production and cellular uptake of sAPP.

[1]  E. Masliah,et al.  Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Nyengaard,et al.  Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing , 2012, The Journal of Neuroscience.

[3]  R. Vink,et al.  Soluble amyloid precursor protein α reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats , 2006, Brain Research.

[4]  B. Hyman,et al.  Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  C. Haass.  Take five—BACE and the γ‐secretase quartet conduct Alzheimer's amyloid β‐peptide generation , 2004 .

[6]  C. Haass.  Take five--BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation. , 2004, The EMBO journal.

[7]  P. Nissen,et al.  Ligands bind to Sortilin in the tunnel of a ten-bladed β-propeller domain , 2009, Nature Structural &Molecular Biology.

[8]  J. Nyengaard,et al.  Sorting by the Cytoplasmic Domain of the Amyloid Precursor Protein Binding Receptor SorLA , 2007, Molecular and Cellular Biology.

[9]  B. Hyman,et al.  Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease. , 2000, The Journal of biological chemistry.

[10]  S. Moestrup,et al.  Propeptide cleavage conditions sortilin/neurotensin receptor‐3 for ligand binding , 1999, The EMBO journal.

[11]  S. Thirup,et al.  GGA Autoinhibition Revisited , 2010, Traffic.

[12]  Yonghe Li,et al.  The Low Density Lipoprotein Receptor-related Protein 1B Retains β-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-β Peptide Production* , 2004, Journal of Biological Chemistry.

[13]  Vanessa Schmidt,et al.  Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. , 2006, Biochemistry.

[14]  H. Feldman,et al.  Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin , 2010, Neuron.

[15]  P. Saussoy,et al.  Evaluation of real-time PCR data. , 2004, Journal of biological regulators and homeostatic agents.

[16]  P. Madsen,et al.  The sortilin cytoplasmic tail conveys Golgi–endosome transport and binds the VHS domain of the GGA2 sorting protein , 2001, The EMBO journal.

[17]  M. Mattson,et al.  Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein , 1993, Neuron.

[18]  C. Kelche,et al.  A secreted form of the β-amyloid precursor protein (sAPP695) improves spatial recognition memory in OF1 mice , 2004, Neurobiology of Learning and Memory.

[19]  Rudolph E Tanzi,et al.  Diabetes-Associated SorCS1 Regulates Alzheimer's Amyloid-β Metabolism: Evidence for Involvement of SorL1 and the Retromer Complex , 2010, The Journal of Neuroscience.

[20]  Yonghe Li,et al.  The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. , 2004, The Journal of biological chemistry.

[21]  B. Hyman,et al.  LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation , 1995, Cell.

[22]  J. Nyengaard,et al.  Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury , 2007, Nature Neuroscience.

[23]  L. Jen,et al.  Cell-specific expression of β-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes , 1997 .

[24]  D. Selkoe,et al.  Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1 , 2008, Neural Development.

[25]  A. Patel,et al.  Cell-specific expression of beta-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes. , 1997, Brain research. Molecular brain research.

[26]  H. Okada,et al.  BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin* , 2011, The Journal of Biological Chemistry.