Characterisation and imaging of A-beta plaque formation and associated pathologies in transgenic mice

• Antragstellerin: Professorin Dr. Melanie Meyer-Luehmann
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2009 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 117513724

A number of degenerative neurological and systemic diseases are characterized by the aberrant polymerization and accumulation of specific proteins in tissues. In the nervous system, these proteopathies include Alzheimer s disease (AD) and Parkinson s disease (PD) among others (Selkoe, 2003). In order to provide a meaningful therapy, it is essential to understand the pathogenesis of these diseases, particularly in their early stages. To study AD, a variety of transgenic mouse models have been generated which develop several lesions similar to those seen in AD, such as diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. There are common pathological features between many neurodegenerative diseases such as abnormal protein aggregation and neuroanatomical changes. Since some patients show clinical and pathological features of Alzheimer’s and Parkinson’s disease, it has been speculated that both diseases share overlapping pathogenic pathways and might even influence each other.We have previously shown that intracerebral injection of Aβ-containing human or transgenic mouse brain extracts can induce cerebral amyloidosis and associated pathology in APP transgenic mice (Meyer-Luehmann et al., 2006). Using in vivo multiphoton microscopy, we were recently able to visualize later stages of plaque formation and the morphological neuronal changes associated with it (Meyer-Luehmann et al., 2008).The present grant proposal contains 2 related but distinct projects. We suggest visualizing and characterizing early stages of Aβ plaque formation by combining seeding and 2-photon microscopy with measurements of spontaneous neuronal activity during these early stages of plaque formation. Furthermore, we will test the idea that α-synuclein could be a potent candidate for an amyloid inducing agent. Since the majority of AD cases are initiated by unknown causes, an understanding of the mechanisms involved in the instigation and propagation of abnormal Aβ forms in vivo will shed light on the origins of the disease, and will suggest new pathways to preventive or disease-modifying treatments.

• DFG-Verfahren: Emmy Noether-Nachwuchsgruppen
• Großgeräte: Konfokales Zweiphotonen-Laserscanning-Mikroskop
• Gerätegruppe: 5090 Spezialmikroskope