title: Amyloid-β Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease.
abstract: The mechanisms leading to amyloid-β (Aβ) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Aβ plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Aβ precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Aβ40 and Aβ42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Aβ accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Aβ species.
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Alvaro
authors.initials: A
authors.lastname: Barrera-Ocampo
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Sönke
authors.initials: S
authors.lastname: Arlt
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Ursula
authors.initials: U
authors.lastname: Hartmann
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Berta
authors.initials: B
authors.lastname: Puig
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Petra
authors.initials: P
authors.lastname: Zürbig
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O) dsepulve@uke.de.
authors.forename: Diego
authors.initials: D
authors.lastname: Sepulveda-Falla
authors.affiliation: From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
authors.forename: Holger
authors.initials: H
authors.lastname: Jahn
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011509:Proteoglycans / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D011509:Proteoglycans; C504369:SPOCK1 protein, human
keywords: APP Swedish mutation; Alzheimer disease; Early endosomes; Neuritic plaques; Testican-1; β-Amyloid