Background & Research

Alzheimer's disease (AD) is the most common form of dementia and neuropathologically characterized by the accumulation of senile plaques and neurofibrillary tangles in brains of patients.

Fig. 1: Neuropathology of Alzheimer's Disease.

While most cases occur sporadically after the age of 65 years, 5-10 % of the cases are caused by mutations in the genes for ßAPP, and the presenilins that lead to early onset of the disease at ages between 20-60 years. A major constituent of senile plaques is the amyloid ß-peptide (Aß), which derives from the larger ß-amyloid precursor protein (ßAPP) by proteolytic processing. For generation of Aß, ßAPP has to be first cut by an enzyme called ß-secretase resulting in the shedding of the ßAPP ectodomain. A C-terminal fragment that contains the Aß domain (ß-CTF) remains inserted in the cellular membrane. This fragment subsequently can be cleaved by γ-secretase within the transmembrane domain leading to secretion of Aß into extracellular fluids. Alternative to cleavage by ß-secretase, ßAPP can be cleaved by an enzyme called a-secretase. This cleavage occurs in the middle of the Aß domain and precludes the generation of Aß.

Fig. 2: Proteolytic processing pathways of ßAPP

The enzymes involved in proteolytic processing of ßAPP have been identified:

• a-Secretase: Three proteases of the ADAM (A Disintegrin And Metalloproteinase) family can exert a-secretase cleavage of ßAPP that leads to secretion of the large ectodomain and generation of membrane bound C-terminal fragment (a-CTF).
• ß-Secretase: ß-Secretase has been identified as the membrane-bound aspartylprotease BACE (ß-site APP cleaving enzyme) This enzyme cleaves ßAPP at the N-terminus of the Aß-domain, which results in the generation of soluble APP _S -ß and ß-CTF that contains the complete Aß-domain.
  
  Fig. 3: Model of BACE (ß-Sekretase)
  
  
• γ-Secretase: The CTFs generated by a- and ß-secretase are substrates for γ-secretase which cleaves these fragments in the middle of the transmembrane domains to generate p3 and Aß. γ-Secretase is not a single protein entity, but consists of at least four distinct membrane proteins, which are required for enzymatic activity. The presenilin proteins might represent members of a novel class of aspartic proteases that can cleave proteins within cellular membranes.
  
  Fig. 4: Components of the γ-secretase complex
  
  

We are interested in the molecular and cellular mechanisms that are involved in proteolytic processing of ßAPP and the generation of Aß.

We focus on the analyses of subcellular trafficking of AD related proteins including ßAPP, BACE-1, BACE-2, and presenilins.

In order to identify mechanisms that are involved in the regulation of physiological and pathophysiological functions of these proteins we analyze post-translational modifications (phosphorylation, glycosylation, sulphation) and identify interaction partners like lipids and proteins.

Collaborations:

• Christian Haass; Ludwig-Maximilians University Munich; Munich
• Gerd Multhaup; Technische Universität; Berlin
• Richard Killick; King’s College; London; UK
• David Teplow, Harvard Medical School; Boston; USA
• Fred van Leuven; Katholieke Universiteit; Leuven; Belgium
• Michael Famulok; Rheinische Friedrich-Wilhelms-Universität; Bonn
• Konrad Sandhoff; Rheinische Friedrich-Wilhelms-Universität; Bonn
• Michael Heneka; Westfälische Wilhelms-Universität; Münster
• Dieter Lütjohann; Rheinische Friedrich-Wilhelms-Universität; Bonn

Fundings:

• Deutsche Forschungsgemeinschaft (DFG)
• Herbert Reeck Stiftung
• Bonfor