New understanding of the mechanism of neurodegeneration leads to a novel approach to treatment for Alzheimer’s disease

Innovative drug prototype shown to block damaging activity in human cell lines suggests a promising strategy for future therapeutics.

Alzheimer’s is characterised by, amongst other factors, the presence of amyloid, in its various forms, and hyperphosphorylated tau leading to cognitive impairment. The research published suggests that a previously undiscovered mechanism in a key group of neurons affected in a neurodegenerating brain is the key driver of the continuing cycle of neuronal cell death. It could be possible to halt the progression of the disease by intercepting this mechanism.

Researchers at Neuro-Bio have now validated a novel theory for the continuing cycle of neuronal death that typifies Alzheimer’s and other neurodegenerative disorders such as Parkinson’s and Motor Neurone Disease. The key driver is a 14 amino acid peptide (‘AChE peptide’) that originates from acetylcholinesterase (AChE), an enzyme essential in breaking down a well-known chemical messenger between neurons, but increasingly recognised as a signalling molecule with non-enzymatic functions. Although the existence of the AChE peptide and its link to neurodegeneration have been previously proposed in Professor Greenfield’s work, these are the first reports of its detection in both human and rat brain and its actions in driving an Alzheimer-like biochemical profile.

The two consecutive papers in Neuropharmacology report raised levels of the novel peptide in Alzheimer’s midbrain and cerebrospinal fluid compared with controls, and demonstrate that, in vitro, the peptide drives production of both amyloid and hyperphosphorylated tau. In the first paper, the damaging effects of either the AChE peptide or amyloid are shown to be blocked by a novel prototype drug (NBP-14), a cyclised form of the AChE peptide. NBP-14 intercepts the action of the AChE peptide on the alpha-7 nicotinic receptor, which is found on the outer surface of neuronal cells. In the second paper, the effects of the AChE peptide and their blockade by NBP-14 are demonstrated in ex vivo rat basal forebrain, using real-time optical imaging of large-scale, transient ‘neuronal assemblies’.

Professor Susan Greenfield, CEO of Neuro-Bio and senior author on both papers, commented: “These publications are the culmination of some 40 years research from our lab building up a picture indicating that the naturally occurring AChE peptide is a pivotal signalling molecule in a mechanism underlying Alzheimer’s and related disorders. We are encouraged by the potential for the prototype compound NBP-14 to block the activity of this peptide and also by the possibility of monitoring the peptide as a biomarker for early, even pre-symptomatic diagnosis.”

Professor Gary Small of the Brain Research Institute, University of California, Los Angeles, and member of the Neuro-Bio Scientific Advisory Board added: “This recent work showing that a peptide derived from acetylcholinesterase is elevated in the Alzheimer brain and that a synthetic version of this peptide enhances calcium influx and eventual production of amyloid beta and tau phosphorylation via an allosteric site on the alpha-7 nicotinic receptor is extremely exciting. The fact that a synthetic cyclic version of this peptide is neuroprotective makes this innovative therapeutic approach highly promising.”

Professor Margaret Esiri of the Neuropathology Dept at the John Radcliffe Hospital Oxford and member of the Neuro-Bio Scientific Advisory Board commented: “After quite a number of years of research this is an important staging-post at which Neuro-Bio can develop aspects of the work in new directions and with new confidence. This I can see is really exciting and gives new opportunities to increase the pace of the research.”

Professor Terry Sejnowski, Investigator at the Howard Hughes Medical Institute and Francis Crick Professor at The Salk Institute said: “Any new approach to Alzheimer’s disease, which is increasing in prevalence as we live longer, that shows as much promise as this new peptide should be quickly brought to the attention of the scientific community. The dominant focus on beta amyloid has side-tracked the scientific community and the potential new direction will be a surprise to Alzheimer’s researchers.”