title: Amyloid-precursor-protein-lowering small molecules for disease modifying therapy of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD.
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Germany ; Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Sina Cathérine
authors.initials: SC
authors.lastname: Rosenkranz
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Germany ; Department of Vascular medicine, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Geissen
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Härter
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Szalay
authors.affiliation: Institute of Neuropathology, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Vogel
authors.affiliation: European Screening Port GmbH, Hamburg, Germany.
authors.forename: Stephen
authors.initials: S
authors.lastname: Smith
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases