The drug candidate J147 was able to reverse memory deficits and improve several aspects of brain function in mice with advanced symptoms of Alzheimer's disease, according to a new study.
Previous studies have demonstrated that several compounds are able to prevent or delay onset of AD-like symptoms in young mice but that does not mimic the situation in humans, where symptoms usually precede the diagnosis.
To address this problem, researchers used older mice, whose symptoms of
are already at an advanced stage. Treating these mice with J147 improved their memories in several assays. Examination of the brains of the J147-treated mice showed decreases in proteins associated with cell death and increases in proteins that form the connections responsible for learning and memory.
In a separate but related set of studies using a different model of memory impairment, both J147 and donepezil (Aricept) improved short term memory while only J147 improved spatial memory. Importantly, the combination improved another form of memory commonly lost in Alzheimer's disease.
The activity of J147 in these mice could be seen at a molecular level. Marguerite Prior, the lead scientist on this study explained, "During treatment we saw an increase in neurotrophic factors including nerve growth factor (NGF) and brain-derived growth factor (BDNF) which are essential for correct memory function. This explains how J147 is working."
David Schubert, who heads the Cellular Neurobiology Laboratory at the Salk Institute where the work was carried out, credits the novel drug discovery approach that they have developed for the exceptional therapeutic efficacy of J147 in AD mice.
Schubert says that "our approach to screening drugs is very different from that currently used by pharmaceutical companies. AD is a complex disease associated with old age, and our goal is to make drugs like J147 that reduce the multiple toxicities associated with the disease, not just one. We believe that J147 is the best AD drug candidate in the pipeline and will be effective if we can get it into the clinic".
Citation: Marguerite Prior, Richard Dargusch, Jennifer L Ehren, Chandramouli Chiruta and Dave Schubert, 'The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice', Alzheimer's Research&Therapy 2013, 5:25 doi:10.1186/alzrt179 (open access)