Mechanisms of neurodegeneration: Towards a cure for Alzheimer’s disease

Abstract

Neurodegeneration in Alzheimer’s disease (AD) entails dysregulated signalling in and between neurons. As such, the search for new therapies capable of normalising these signalling dysfunctions in AD is a promising strategy to treat the disease. Therefore we set out to validate an in-house high-throughput phenotypic screening system featuring AD-like signalling deregulations. This model system was then used to identify a novel chemical class (REM), which effectively counteracted the AD-like signalling dysfunctions in the model and hence conveyed neuroprotection. Following the identification of REM, we set out to investigate the mechanism of action underlying the compound’s neuroprotective properties using conventional AD in-vitro and in-vivo models. REM was found to modulate a transport protein controlling the subcellular localisation of a GTPase. The resulting change was found to normalise the aberrant signalling processes and thereby also detrimental neuronal hyperexcitability. In addition behavioural deficits were rescued in transgenic AD mice. Taken together, REM, a novel modulator of deregulated cellular signalling cascades, constitutes a promising new therapy for AD.