Amyloid beta-protein deposition and toxicity in animal models of Alzheimer's disease

• Applicant: Professor Dr. Dietmar Thal
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2007 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 42328123

The APP-transgenic mouse is an animal model for Alzheimer's disease (AD). Amyloid b-protein (Aβ) aggregates are produced in these mice and induce dendritic alterations of pyramidal neurons. Using mouse models for intra- as well as for extracellular Aβ-deposition we were able to show that extracellular but not intracellular Ab-aggregates induce dendritic degeneration and synapse loss. We found presumably physiologically occurring Ab-aggregates in the brain of wildtype mice and control patients. In AD cases and in APP-transgenic mice developing signs of neurodegeneration Ab-aggregates with an abnormal conformation were identified. To further characterize these abnormal Aβ-aggregates human AD and control brain tissue will be analyzed biophysically and biochemically for distinct Aβ-aggregate conformations. To test whether abnormal Ab-aggregates are capable of supporting the development of AD-related neurofibrillary pathology with intracellular t-protein aggregates different APP-transgenic mouse models will be crossbred with t-transgenic mice. It will be analyzed which type of Aβ-expression influences t-pathology. Finally, young immunized APP-transgenic mice showed less dendritic pathology than non-immunized ones. We want to confirm this preliminary finding by analyzing the synapse density and the number of 3 dystrophic dendrites in these mice. In so doing, we want to further clarify the mechanisms of Ab- toxicity and to verify the value of possible therapeutic targets for AD.

• DFG Programme: Research Grants