Impact of TSPO activation on Abeta-induced synaptotoxic effects - focus on learning and memory-related processes

• Applicant: Professor Dr. Gerhard Rammes, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 340549550

Memory impairment and progressive cognitive decline are the main symptoms of Alzheimer Disease (AD), a neurodegenerative disorder with increasing incidence among elderly people. The most obvious pathological feature of AD is the accumulation of beta-amyloid peptides (Abeta) in the brain, and these peptides are thought to underlie early deficits in synaptic plasticity and the resulting cognitive impairment. There is increasing clinical evidence that depression is a common antecedent of Alzheimer disease and may be an early manifestation of dementia suggesting partly overlapping biological mechanisms of these diseases. Indeed, perturbation of energy and protein homeostasis facilitating neurodegenerative processes is proposed as the unifying mechanism of depression and cerebral aging.The mitochondrial translocator protein (18 kDa) (TSPO) promotes neurosteroidogenesis in neurons and astrocytes. Interestingly, TSPO ligands have been shown to be neuroprotective and might be beneficial in the treatment of neurological and psychiatric disorders. In a recent translational study, we demonstrated that the selective and high-affinity TSPO ligand XBD173 displayed antipanic and anxiolytic efficacy in rats and humans via neurosteroidogenesis.The primary goal of this application is to elucidate the molecular mechanisms and functional consequences of TSPO activation. The fundamental question on the physiological level is: does exposure to XBD173 exert early (neuro)protective effects in the pathophysiology of AD? To address this question, we will employ methods from molecular and cell biology, monitoring the activity of neurons and animal behaviour.More specifically, XBD173 will be tested for its potential to reverse the toxic effect of Abeta on spine density, neuronal circuits and Abeta-induced synaptotoxicity against the induction of long-term potentiation (LTP), a cellular correlate for learning and memory. Finally, we will employ an animal model of AD to evaluate XBD173 for its ability to modify AD at early and late stages by reducing protein aggregates or the levels of toxic protein species and enhance cognition. TSPO knockdown/knockout models will serve to answer the question for direct and TSPO-specific mechanisms.Most previous studies have been conducted using Abeta1-40 or Abeta1-42 peptides. However, recently other Abeta species are receiving considerable attention as possible pathogens in AD due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Therefore, we will include the toxic Abeta species pyroglutamate-modified Abeta-(Abeta pE3) and nitrated Abeta (3NTyr10-Abeta).Altogether, the present proposal intends to reveal any potential beneficial mechanisms of XBD173 regarding the pathophysiology in AD such as neuronal dysfunction and reduced memory processes.

• DFG Programme: Research Grants