GRK 1123 - Learning and Memory

|| Home || Positions || Contact ||

GRK 1123:

Cellular Mechanisms of Learning and Memory Consolidation
in the Hippocampal Formation

| Home

| News

| Research

| Study Program

| Events

| Faculty

| Students

| Links

This Research Training Group is funded by the German Research Council DFG

Imprint & Disclaimer

AG Ahnert-Hilger	AG Behr	AG Geiger	AG Haucke	AG Heinemann/ Kempter
AG Multhaup	AG Wulczyn	AG Rosenmund	AG Schmitz/ Brecht	AG Sigrist

Prof. Dr. rer. nat. Gerd Multhaup
Institut für Chemie-Biochemie
Freie Universität Berlin
Thielallee 63
14195 Berlin
multhaup@chemie.fu-berlin.de

Title

Toxicity of the amyloid Aß peptide: a possible role in the nucleus

Question of the project

A broad range of neurodegenerative disorders such as Alzheimer’s disease (AD) share the common feature of neuronal damage that may be caused by toxic, aggregation-prone proteins. The clinical condition of AD patients is paralleled by a synaptic pathology, which underlies the weakening in learning and memory in AD.

Non-fibrillar aggregates have been shown to be toxic to cells in culture and in vivo and to impair synaptic functions. In addition, we found that mechanisms such as oligomerization of the amyloid precursor protein (APP) itself, APP heterointeractions with APP related proteins APLP1 and APLP2 and the beta-secretase (BACE) directly influence the production of toxic peptides and were identified as risk factors.

Specific questions to be addressed are:

What determines the particular toxic effect and what is the exact mechanism?
What are the primary targets to the toxic forms and how is toxicity mediated to specific cells?

Scientific background

A model of pathological intraneuronal Aß oligomers was proposed, based on the occurrence of APP homodimers (Beher et al., 1996; Kaden et al., 2008; Scheuermann et al., 2001) and stabilized Aß dimers (Schmechel et al., 2003). An interaction motif within the Aß domain of the transmembrane sequence mediated homodimeric interactions of APP and strongly influenced Aß42 production (Munter et al., 2007). Early studies described soluble Aß42 oligomers as the major cause for neuronal loss in AD brains. We were able to show that the motif GxxxG is not only involved in Aß generation but also that Gly residues G29 and G33 are key residue influencing aggregation and toxicity of Aß42 (Munter et al., 2007; Harmeier et al., 2009).

Surprisingly, G33 substitutions could uncouple oligomerization from toxicity and LTP inhibition (Harmeier et al., 2009). Our results imply the existence of different types of Aß strains, some causing toxic effects and others aggregating into oligomers without adopting toxic conformations. This novel knowledge on toxic oligomers and non-toxic forms has provided us with excellent tools to investigate the primary targets to the toxic forms of Aß and to answer the question how is Aß toxicity linked to cellular mechanisms of learning and memory.

Beher D, Hesse L, Masters CL, Multhaup G (1996) Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I. J Biol Chem 271:1613-1620.
Harmeier A, Wozny C, Rost BR, Munter LM, Hua H, Georgiev O, Beyermann M, Hildebrand PW, Weise C, Schaffner W, Schmitz D, Multhaup G. (2009) Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity. J Neurosci. 2009 Jun 10;29(23):7582-90.
Kaden, D., Munter, L.M., Joshi, M., Treiber, C., Weise, C., Bethge, T., Voigt, P., Schaefer, M., Beyermann, M., Reif, B., et al. (2008). Homophilic interactions of the amyloid precursor protein (APP) ectodomain are regulated by the loop region and affect beta-secretase cleavage of APP. J Biol Chem 283, 7271-7279.
Munter, L.M., Voigt, P., Harmeier, A., Kaden, D., Gottschalk, K.E., Weise, C., Pipkorn, R., Schaefer, M., Langosch, D., and Multhaup, G. (2007). GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42. EMBO J 26, 1702-1712.
Scheuermann S, Hambsch B, Hesse L, Stumm J, Schmidt C, Beher D, Bayer TA, Beyreuther K, Multhaup G (2001) Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer's disease. J Biol Chem 276:33923-33929.
Schmechel A, Zentgraf H, Scheuermann S, Fritz G, Pipkorn R, Reed J, Beyreuther K, Bayer TA, Multhaup G (2003) Alzheimer beta-amyloid homodimers facilitate A beta fibrillization and the generation of conformational antibodies. J Biol Chem 278:35317-35324.

Objectives

In the present project we have discovered a possible role for Aß in gene regulation, which could either represent a new or an abnormal function of Aß. A possible function of APP in nuclear signaling was suggested for AICD (APP intracellular domain), which has been shown to translocate into the nucleus as a complex with the neuronal adaptor protein Fe65. Fe65 was shown to bind and to stabilize AICD and to associate with the histone acetyltransferase Tip60. AICD was reported to up-regulate several genes, such as KAI1, APP, BACE, neprilysin and others, whereas the lipoprotein receptor LRP1 is negatively regulated by AICD. Our novel hypothesis is that not only AICD but also Aß has a role in gene regulation. Recent results showed that Aß oligomers were rapidly internalized and transported within the cell from the cytoplasm into the nucleus. However, the exact transport mechanism remains still unclear.

We conclude that Aß42 can have a specific transcriptional regulatory function. Our data imply that deregulation of Aß target genes could be an alternative pathway for Aß-induced neurotoxicity.

The overall aim of this project is to improve our understanding of mechanisms of APP in mediating toxicity through nuclear signaling. The objectives based on our recent findings are:

To understand how does Aß induce gene regulation
How do Aß dimers and/ or tetramers cause neurotoxicity
Which genes associated with learning/memory defects are affected by Aß

Methods

molecular biology (incl. molecular cloning, RNA isolation, qRT-PCR)
biochemical (incl. subcellular fractionation, western blot, ELISA, ChIP)
cell biological (transfection of neuronal cell lines, confocal microscopy, cry-EM)
biophysical (BIAcore, MALDI-MS, ICP-MS)

Dissertation topics

Identification and characterization of genes and products thereof causing learning and memory defects in AD
Analysis of the relationship between nuclear import of Aß and toxic effects such as LTP inhibition and neuronal cell death

Cooperation with other Members

AG Schmitz: Electrophysiological and optical methods to study the mechanisms of synaptic transmission in mouse brain sections and primary neurons.
AG Haucke: Biochemical analysis of vesicular structures in neuronal cells
AG Sigrist: Stimulated Emission Depletion microscopy, STED microscopy, for higher resolution improvements over confocal microscopy to image intracellular transport mechanisms

Scholarship Holder:

Anja Harmeier (April 2005-March 2008)
Christian Barucker (since April 2008)

AG Ahnert-Hilger	AG Behr	AG Geiger	AG Haucke	AG Heinemann/ Kempter
AG Multhaup	AG Nitsch/ Wulczyn	AG Rosenmund	AG Schmitz/ Brecht	AG Sigrist