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Jun 30, 2016
 |  BC Innovations  |  Targets & Mechanisms

AChE revisited

Why Neuro-Bio thinks it's time to revisit the role of AChE in AD

Neuro-Bio Ltd. has identified a peptide derived from AChE - the enzyme responsible for breaking down acetylcholine - and believes the fragment is the main pathological driver in Alzheimer's disease, acting upstream of β-amyloid and tau in the brain centers hit earliest in the disease.

The company, which was formed in 2013, is developing inhibitors of the peptide to create a disease-modifying therapy, and is seeking investors to help fund preclinical studies.

Its approach departs from the strategy behind the standard of care in AD, in which AChE inhibitors are used to enhance levels of ACh in the synaptic cleft, boosting neurotransmission to compensate for the loss of cholinergic neurons that commonly occurs in the disease.

CEO Susan Greenfield told BioCentury that the marketed drugs provide only modest and transient symptomatic relief, and because their goal is to eke out more transmission from the remaining cells, they don't address the root cause of the disease.

Indeed, most companies have moved on to targeting molecules thought to drive the pathology - in particular β-amyloid and tau, each of which forms toxic protein aggregates in AD brains.

But Greenfield said Neuro-Bio has a fresh take on AChE that places a cleavage product of the enzyme at the center of a mechanism that drives the earliest events, including deposition of β-amyloid and tau (see Figure: Triggering AD).

"My view is that amyloid and tau are secondary in the cascade," said Greenfield, adding that because both markers form aggregates in many brain centers, neither can explain why degeneration begins in specific, localized regions.

"One of the problems with the amyloid theory is that it is potentially ubiquitous in the brain, yet we know only certain cells are lost," she said. "We've pinpointed a much more specific mechanism in brainstem and midbrain neurons that leads to the generation of amyloid and tau downstream."

At least 20 studies have shown that AD pathology arises in a collection of deep brain centers, including the areas that produce ACh, serotonin, dopamine and norepinephrine. Greenfield said two features unite the cells: they all express AChE, even the non-cholinergic cells, and they have a common developmental origin. "These cells have a different embryological provenance from the rest of the cells in the brain: they come from the basal plate, not the alar plate. Our suggestion is that gives them different properties that make them more vulnerable" to a variety of insults.

One such property, she said, is that the cells retain a higher sensitivity to trophic factors in adulthood than those in higher...

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