A novel approach to enhance cognitive function and promote synaptic plasticity
Alzheimer's disease (AD) is a severe burden on the Australian health care system and affects about 30% of the population over 65 years of age. While we have made significant advances in understanding the mechanisms of AD pathology, we are yet to develop an effective therapeutic that tackles not only the issues of memory loss but also the underlying brain neurodegeneration, such as the degeneration of the basal forebrain cholinergic neurons. Our lab has generated a cell permeable peptide (c29) that enhances the signalling potential of the low reserves of growth factors, a feature of the brains of people with AD, as well as promoting neuronal survival. This project will make new versions of the c29 peptide to improve its drug-like properties and will test the ability of c29 to enhance cognitive functioning in mice, with the aim of demonstrating the promise of this molecule as a therapeutic to treat AD.
Neurotrophins are a family of proteins that promote synaptic plasticity, neuronal survival, neurogenesis and differentiation. They signal by binding to a specific tropomysin kinase (Trk) receptor that promotes trophic signalling, as well as to the p75 neurotrophin receptor (p75NTR), which mediates neuronal cell death. Our lab has identified a core-signalling motif of the p75NTR intracellular fragment and generated a cell-permeable peptide mimic called c29. c29 provides a novel way to enhance Trk-mediated signalling at low neurotrophin concentrations.
We have previously shown that c29 can mediate trophic effects within the central nervous system via peripheral administration, suggesting that the peptide is stable enough to cross the blood brain barrier (BBB).
To extend our findings, we have generated a mouse line in which c29 can be produced in time and cell-specific manner. We have intercrossed this line with another line resulting in expression in the cholinergic neurons of the basal forebrain and peripheral nervous system, thereby allowing us to test the effects of c29 on basal forebrain function. We have found that the c29 mice have different results from their control littermates on several learning and memory tests. We are continuing to investigate these mechanisms.
In parallel we have been testing the effects of c29 peptides that have altered properties that are designed to increase their biostability while retaining function. Preliminary results suggest we will identify an optimized c29 peptide that has increased biostability, which we will then use to test the ability of c29 to rescue cognitive impairment in a cognitively impaired mouse model.
We had chosen to use a model in which the neurotrophin BDNF was expressed at lower levels (as occurs in aged humans), however these mice breed poorly and so far we have not found a robust cognitive deficit. We are currently investigating the used of aged mice.
Dr Camara is currently a postdoctoral fellow at the Queensland Brain Institute, University of Queensland.