gms | German Medical Science

57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

12. - 15.09.2012, Erlangen

Banner: 57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie

Presenilin is the molecular target of γ-secretase modulators, an emerging class of therapeutics for Alzheimer’s disease

Meeting Abstract

  • presenting/speaker Thorsten Jumpertz - Medical School Duesseldorf, Neuropathology, Duesseldorf, Germany
  • Andreas Rennhack - caesar, Chemical Biology, Bonn, Germany
  • Julia Ness - Medical School Duesseldorf, Neuropathology, Duesseldorf, Germany
  • Isabella Ogorek - Medical School Duesseldorf, Neuropathology, Duesseldorf, Germany
  • Bruno Bulic - caesar, Chemical Biology, Bonn, Germany
  • Sascha Weggen - Medical School Duesseldorf, Neuropathology, Duesseldorf, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnOP17

DOI: 10.3205/12dgnn017, URN: urn:nbn:de:0183-12dgnn0173

Veröffentlicht: 11. September 2012

© 2012 Jumpertz et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

A crucial step in the pathogenesis of Alzheimer's disease (AD) is the accumulation and aggregation of hydrophobic amyloid peptides (Aβ42) in the brain. γ-Secretase modulators (GSMs) are small molecules that lower the cellular production of Aβ42 peptides, but spare other vital physiological functions of the γ-secretase enzyme. Recently, potent GSMs with favorable pharmacological properties have been reported in two major structural classes: carboxylic acids with structural similarities to non-steroidal anti-inflammatory drugs (acidic GSMs) and compounds based on bridged aromatics that lack a carboxylic acid group (non-acidic GSMs).

Question: GSMs belong to the most promising drugs in clinical development for AD. However, their molecular target(s) and their mechanism of action are only poorly defined.

Methods: We used a chemical biology approach with photo-probes to identify the pharmacological target of GSMs. These probes can be activated by UV-light and then form a covalent bond with any protein in their immediate vicinity, which allows to trap and purify the target protein(s) of a compound of interest. In addition, a fluorescent GSM derivative was applied to evaluate the cell permeability and intracellular distribution of GSMs.

Results: By combining photo-labeling with affinity purification, we have demonstrated that a photo-probe based on an acidic piperidine GSM bound to the N-terminal fragment of presenilin-1 (PSEN1), the catalytic subunit of the γ-secretase complex. Labeling was not observed for the γ-secretase substrate APP or any of the other γ-secretase subunits. However, binding of the photo-probe to PSEN1 was efficiently competed by non-acidic GSMs suggesting a shared mode of action. This was confirmed with a second photo-probe based on non-acidic purine GSMs, which similarly bound to PSEN. In live cells, the distribution of the fluorescent GSM appeared to resemble the subcellular localization of PSEN1, while only diffuse background staining was observed in PSEN1/PSEN2 double-knockout fibroblasts.

Conclusions: Our results indicate that potent and clinically relevant GSMs target PSEN, the catalytic subunit of the γ-secretase complex. These data confirm that GSMs modulate the generation of the toxic Aβ42 peptides and the enzymatic activity of γ-secretase through direct interaction with the protease, and are a critical step to further elucidate the molecular mechanism of these putative AD therapeutics.