The mechanism behind neurodegeneration

Researchers at biotech company Neuro-Bio claim that a previously undiscovered mechanism in a key group of neurons affected in a neurodegenerating brain is the driver of the continuing cycle of neuronal cell death. They say it could be possible to halt the progression of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and motor neurone disease by intercepting this mechanism.

The key driver is said to be 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. While the existence of the AChE peptide and its link to neurodegeneration have been previously proposed, these are the first reports of its detection in both human and rat brain and its actions in driving an Alzheimer-like biochemical profile.

Writing in the journal Neuropharmacology, the researchers 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 amyloid and hyperphosphorylated tau — both of which are characteristics of Alzheimer’s. In their first paper, the damaging effects of either the AChE peptide or amyloid are shown to be blocked by a novel prototype drug (NBP14), a cyclised form of the AChE peptide. NBP14 intercepts the action of the AChE peptide on the alpha-7 nicotinic receptor, which is found on the outer surface of neuronal cells. In their second paper, the effects of the AChE peptide and their blockade by NBP14 are demonstrated in ex vivo rat basal forebrain, using real-time optical imaging of large-scale, transient ‘neuronal assemblies’.

“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,” said Neuro-Bio CEO Professor Susan Greenfield, the senior author on both papers. “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.”