A key to the “AChE” of Alzheimer's

OXFORD, U.K.—The role of amyloid plaques and hyperphosphorylated tau in the development of Alzheimer's is well known, but new insight into the nature of their production has recently come to light. Biotech company Neuro-Bio Limited published details on a new model for the mechanism of neurodegeneration leading to Alzheimer's this week in Neuropharmacology.

Researchers at Neuro-Bio have validated a theory explaining the ongoing cycle of neuronal death seen in neurodegenerative disorders such as Alzheimer's, Parkinson’s and motor neurone disease. The culprit is a 14 amino acid peptide (AChE peptide) originating from the enzyme acetylcholinesterase (AChE), which is essential in breaking down a chemical messenger between neurons and is now increasingly recognized as a signaling molecule with non-enzymatic functions. The link between the AChE peptide and neurodegeneration has previously been established, but these two papers are the first to cover its presence in human and rat brains, as well as its role in driving an Alzheimer-like biochemical profile.

Professor Susan Greenfield, CEO of Neuro-Bio and senior author on both papers, remarked that: “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 signaling 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.”

The Neuro-Bio team found raised levels of the AChE peptide in Alzheimer's midbrain and cerebrospinal fluid, compared to controls, and demonstrated that in vitro, it drives production of amyloid and hyperphosphorylated tau. The first paper reported that the deleterious effects of either the AChE peptide or amyloid can be blocked by NBP-14. A novel prototype drug and a cyclized 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. The paper “Pharmacological profiling of a novel modulator of the alpha-7 nicotinic receptor: Blockade of a toxic acetylcholinesterase-derived peptide increased in Alzheimer brains” was published online March 1, and also noted that NBP-14 “is neuroprotective against the toxicity not only of its linear counterpart but also of amyloid beta, thereby opening up the prospect for novel therapeutics.”

The second paper explained that the effects of the AChE peptide and its impediment by NBP-14 are demonstrated in ex-vivo rat basal forebrain, using real-time optical imaging of large-scale, transient ‘neuronal assemblies.’

Neuro-Bio explains on its site that the cells that comprise the 'hub' of the brain “originate from a distinct part of the early embryo brain, the basal plate, whereas other brain cells derive from the alar plate. Unlike all other brain cells, the 'hub' cells retain sensitivity to developmental chemicals usually only released, and beneficial, in the developing brain. When compared to developing fetal/neonatal brain cells, mature, adult brain cells respond differently to the same developmental chemicals, which, if released inappropriately in maturity as a result of brain damage in the different, mature brain landscape, are toxic, causing cell death instead of assisting in brain cell development. This brain cell damage causes additional release of the now-toxic chemical in the mature brain and the relentless cycle of neurodegeneration.”

“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,” Prof. Gary Small of the Brain Research Institute, University of California, Los Angeles, and member of the Neuro-Bio Scientific Advisory Board, said in a press release.