A new drug that seems to actively reduce the damage wrought in the brain by Alzheimer disease (AD) could represent a promising new therapeutic strategy for this neurodegenerative disease.

One of the hallmarks of AD pathology is the formation in the brain of abnormal protein aggregates, composed of tangles of tau protein and plaques of improperly cleaved amyloid-β peptide (Aβ). Another key indicator is the dysfunction of acetylcholine-based signaling in key regions of the brain due to neuronal death, and researchers have developed several therapeutic strategies that attempt to remedy the neurological and cognitive symptoms of AD by targeting these pathways but without necessarily repairing the effects of AD at the cellular level.

In a recent article from Neuron, the research group of University of California at Irvine investigator Frank LaFerla describes the testing of a new acetylcholine receptor agonist, AF267B, in a transgenic mouse model that shows many of the key pathological indicators of human AD, including plaque and tangle formation (2 March). AF267B activates a specific subclass of acetylcholine receptor commonly found in the hippocampus and cerebral cortex, two regions typically affected by AD pathology.

At 6 months of age these mice typically display strong cognitive and memory deficits. However, 8 weeks of treatment with AF267B considerably improved the animals' performance in spatial memory tests like the Morris water maze. Closer inspection of the brains of treated animals revealed dramatic reduction in the formation of Aβ plaques and tau protein tangles in the hippocampus and cortex, suggesting that the drug is actively inhibiting the formation of protein aggregates. Subsequent experiments by LaFerla's team demonstrated that the action of this drug results in increased levels of ADAM17, the enzyme that mediates proper processing of the Aβ precursor protein.

Although these findings are promising, AF267B does not effectively target all symptoms of AD pathology; in particular, pathology of the amygdala seems to resist treatment. “It turns out that the levels of this enzyme [ADAM17] appear to be lower in the amygdala compared to the other brain regions,” says LaFerla, explaining why these plaques remain largely unaffected. All the same, this drug represents an important step forward—an AD treatment that actually targets the disease and not just the symptoms—and LaFerla's team is now engaged in further exploration of this drug's clinical potential: “The main question [now] relates to how long lasting the effects of this compound are... [and] how quickly does the pathology return if we stop dosing?”