Effects of anle138b treatment on amyloid-β neurotoxicity
von Carolina Thomas
Datum der mündl. Prüfung:2019-08-14
Erschienen:2020-10-02
Betreuer:Prof. Dr. Jeong Seop Rhee
Gutachter:Prof. Dr. Nils Brose
Gutachter:Prof. Dr. Christian Griesinger
Zum Verlinken/Zitieren:
http://dx.doi.org/10.53846/goediss-8233
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Name:CThomas_Diss.pdf
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Zusammenfassung
Englisch
Alzheimer’s disease (AD), the leading etiology of dementia and the fifth cause of death worldwide, has been declared a public health priority by the World Health Organization in 2017. AD is incurable and no treatment can currently modify its natural history. Aberrant accumulation of soluble forms of the amyloid β (Aβ) peptide in AD mouse models has been associated with neuronal loss, hippocampal dysfunction and behavioral alterations, yet data about the underlying molecular synaptic changes are lacking. The novel small molecule anle138b has been found protective when orally administered, even at late stages, in an AD murine model. However, how this promising drug acts in the AD brain at a synaptic level remains unclear. One of the proposed mechanisms is the blockage of amyloid pores, a biophysical phenomenon mostly studied in vitro. Here, I established an in vitro model system of Aβ toxicity by means of incubating murine autaptic hippocampal cultures with synthetic Aβ oligomers, for functional and morphological characterization of AD-like synapses. Interestingly, I observed a marked deficit in synaptic function with no evidence of morphological or biochemical alterations. Furthermore, I preincubated the autaptic neurons with anle138b before Aβ exposure, as performed in other model membranes, to observe a putative inhibition of pore formation. In these experiments anle138b failed in protecting neurons from oligomer synaptotoxicity. In addition, I examined the membrane properties of Aβ-treated autaptic neurons. In contrast to previous literature, even though the oligomeric preparation that I used could induce pore formation in an artificial bilayer, no signs of loss of membrane integrity in neurons were found. Finally, experiments with the enantiomer AllD Aβ indicate that Aβ toxicity is stereospecific, a property that in vitro observed pores lack. In conclusion, I showed that Aβ oligomers impair synaptic glutamate release. These changes might be an early manifestation of AD and constitute a promising disease mechanism that requires further study and confirmation in another disease models. While anle138b failed as pore blocker, it is still possible that in the model system presented here, the autaptic glutamatergic neurons, it could act as an inhibitor of Aβ aggregation and further studies must be performed. Finally, these data suggest that pore formation is a phenomenon occurring mostly in vitro. This highlights the importance of carefully and comprehensively examining the evidence from in vitro studies and the need for a validation in biologically relevant models when studying the mechanisms of human diseases.
Keywords: Alzheimer´s Disease; synaptotoxicity; autaptic cultures; anle138b; amyloid pores
