Emergence of neurodegeneration in Alzheimer’s disease

• Applicant: Professor Dr. Arthur Konnerth
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Anatomy and Physiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505621235

The overarching goal of this research proposal is the discovery of the seminal structural and functional neural defects that initiate neurodegeneration in Alzheimer’s disease (AD). By applying the most sensitive imaging methodologies currently available for in vivo studies in mouse models of β-amyloidosis, such as high-speed LOTOS two-photon imaging and super-resolution STED-SUSHI, we will perform a mechanistic structure-function analysis of impaired neurons and their synaptic contacts over the course of the early stages of Aβ plaque formation. The central hypothesis of the project is that the initial neuronal damage at glutamatergic synapses occurs already at early stages of Aβ plaque formation and involves structural changes at the level of dendritic spines and the associated peri-synaptic astrocytic processes. This hypothesis is based on the observation of early synaptic dysfunction both in AD models in vivo (Busche et al. 2012; Busche et al. 2008; Zott et al. 2019) and in vitro (e.g. (Selkoe 2002)). The relationship between the early synaptic dysfunction and concomitant morphological changes has remained obscure because of technical limitations. In the proposed project, we will largely overcome these bottlenecks by capitalizing on recent technical developments our groups have pioneered, including in vivo glutamate imaging with single-spine resolution and in vitro STED microscopy of astroglial processes. Associating these advances for the first time, we will study the morphology of in vivo assessed dysfunctional individual glutamatergic synapses at nanometer resolution. Thus, a main focus of the study will be the precise mapping of pathological glutamate spillover at the level of individual dendritic spines and the determination of the impact on synaptic function, including the elucidation of the role of astrocytes, a critical target for Aβ in the brain, for the degeneration of neuronal dendrites and spines and their functional impairment.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professor Dr. Valentin Nägerl, Ph.D.