Bedeutung einer TSPO Aktivierung auf Abeta-induzierte synaptotoxische Wirkung - Fokussierung auf Prozesse relevant für Lernen und Gedächtnis
Zusammenfassung der Projektergebnisse
Memory impairment and progressive cognitive decline are the main symptoms of Alzheimer’s disease (AD), a neurodegenerative disorder with increasing incidence among elderly people. The most obvious pathological feature of AD is the accumulation of b-amyloid peptides (Ab; mainly Aβ1-42) in the brain, and these peptides are thought to underlie early deficits in synaptic plasticity and the resulting cognitive impairment. Aβ1-42 oligomers impair cognitive function and inhibit long-term potentiation (LTP), a cellular correlate for learning and memory. There is increasing clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia suggesting partly overlapping biological mechanisms of these diseases. 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. The present study intends to elucidate the molecular mechanisms and functional consequences of XBD173-induced TSPO activation regarding early (neuro)protective effects in the Ab-derived pathophysiology of AD. Aβ1-42, when applied for 90 min to murine hippocampal slices, prevented the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals and reduced the total spine density as assessed in dendrites of CA1 pyramidal neurons. At a concentration of 300nM, XBD173 restored LTP as well as spine density in the presence of Aβ1-42. A more detailed analysis revealed a recovery of stubby, mushroom, thin and filopodia spines. We also tested the toxic Aβ species Aβ1-40, 3NTyr10-Aβ and AβpE3. XBD173 was effective only partly in the presence of AβpE3 and Aβ1-40 and showed no effect against 3NTyr10-Aβmediated toxicity. Chronic (1mg/kg every second day for 3 months) but not acute treatment (1mg/kg one day before testing) with XBD173 ameliorates the cognitive deficits in the ArcAb animals which was maintained in a long-term manner. The widely used anxiolytic diazepam, applied as a reference substance did not show these beneficial effects on cognition. Methoxy-04 staining and ELISA in ArcAb mice treated with chronic XBD173 revealed a reduction of plaque load, plaque count and total Aβ1-42 levels, respectively, in the cortex whereas the prefrontal cortex and hippocampus were not affected. In summary, the present results indicate beneficial effects of XBD173 against an Ab-derived pathology in in vitro as well as in vivo experiments. Furthermore, since chronic treatment with XBD173 ameliorates cognition in a long-term manner, these data let us suggest a disease-modifying effect when applied at early stages of AD. This hypothesis is supported by a XBD173-induced reduction of plaque burden and Aβ levels at least in the cortex.
