A glutamatergic mechanism of β-amyloid dependent astrocytic hyperactivation

• Applicant: Benedikt Zott, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500008564

Although there is ongoing dispute whether β-amyloid (Aβ) accumulation is the main cause of Alzheimer’s disease (AD), it has become apparent that a gradual buildup of Aβ is a prominent feature in the brains of AD patients. Studies in mice and humans reported that Aβ can disturb neuronal and circuit function, even before significant neuronal damage and cell death occur. In more detail, Aβ can directly drive neurons to be more active than in healthy individuals and this neuronal hyperactivity is associated with cognitive impairments. The underlying cellular mechanisms have recently become better understood, when studies in mice demonstrated that soluble Aβ can block glutamate reuptake at synapses. The ensuing overabundance of glutamate in the vicinity of postsynaptic membranes causes neuronal hyperactivation. However, neurons are not the only cell type affected in AD. Astrocytic hyperactivity, i.e. an increased number of calcium (Ca2+)-transients in this glial cell type, has also been observed in in mouse models of AD, but is far less understood. Thus, the main goal of the proposed project will be to investigate the cellular mechanisms of astrocytic hyperactivity in AD. In more detail, we will focus on a connection between Aβ-dependent glutamate accumulation and astrocytic hyperactivity. Our preliminary data suggests that Aβ application can cause astrocytic hyperactivity in vivo. This hyperactivation was based on the activation of metabotropic glutamate receptors, most likely by accumulating glutamate. We plan to test the following hypotheses: Aβ-dependent disruption of glutamate reuptake at synapses causes spill-over (1). This induces astrocytic hyperactivity via metabotropic glutamate receptors especially at astrocytic processes in the vicinity of hyperactive synapses (2). Pharmacologically enhancing glutamate reuptake should reduce neuronal and astrocytic hyperactivity in AD (3). Moreover, astrocytic hyperactivity might precipitate astrocytic structural impairments, apparent at later AD stages (4). Our experimental approach will largely be based on acute and longitudinal two-photon imaging of neuronal and astrocytic Ca2+-transients in acute and chronic mouse models of AD in vivo and in vitro. Additionally, we will employ immunohistochemistry for the ex vivo characterization of astrocytic impairments.Collectively, the proposed project would provide an important platform to improving our understanding of AD pathophysiology by offering a unified cellular mechanism for the emergence of neuronal and glial dysfunction in early disease stages. If astrocytic hyperactivity were driven by an Aβ-dependent accumulation of extracellular glutamate, our findings should encourage the investigation of the molecular mechanism(s) and might stimulate further research into antiglutamatergic disease-modifying drugs.

• DFG Programme: Research Grants