McGill University
McGill University
A novel combined experimental therapy in an Alzheimer's transgenic model
There is a solid body of scientific evidence that the progressive brain accumulation of the peptide named Aβ is central to the Alzheimer's disease (AD) neuropathology. A number of strategies have been designed to lower this burden, in particular in the form of oligomers (molecular repeats of the Aβ amyloid protein). Our laboratory (preliminary evidence) has been able to replicate the reported partial clearance of Aβ in a transgenic model of AD, as communicated by McLaurin and collaborators1. In addition, our laboratory has also revealed that the metabolic cascade responsible for the NGF maturation and degradation is markedly dysregulated in transgenic models of the amyloid pathology and in AD human brain samples. This new finding would explain the vulnerability of NGF-dependent cholinergic neurons to the AD pathology. These neurons are importantly involved in learning and memory mechanisms. Preliminary data from our lab would indicate that these molecular events are unleashed by an Aβ-induced inflammation which, in turn, dysregulates this newly discovered protease cascade controlling the maturation/degradation of nerve growth factor. Preliminary data also would indicate that this dysregulation can be controlled pharmacologically in animal models of AD. We have found remarkable beneficial effects of treating this novel target in conjunction with strategies to remove Aβ oligomers. In consequence, the objective of this research proposal is to explore a combined therapy attacking simultaneously these two targets, i.e. removal of Aβ oligomers and correction of Aβ-induced trophic factor dysmetabolism. Prototypical compounds will be examined in transgenic AD models prior to and after the establishment of the so-called amyloid plaques (i.e. treatments starting at "early" and "late" stages of the AD-like pathology). A multidisciplinary approach will be applied including biochemical, anatomical and behavioral aspects. These investigations have the potential of being applicable in a clinical scenario.