The Pharmaceutical Journal
Vol 276 No 7392 p314
18 March 2006

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Treatment modifies Alzheimer's disease pathology

Treatments that modify the pathology of Alzheimer's disease, rather than simply treating the symptoms, may be approaching human trials, the authors of a study in mice suggest (Neuron 2006;46:671).

Researchers found that the cognitive deficits associated with Alzheimer’s disease — as well as the plaques and tangles linked to its pathology — are reduced by AF267B, a selective agonist for M1 muscarinic acetylcholine receptors.

M1 receptors are the most abundant acetylcholine receptors in the cortex and hippocampus — the two main brain regions that develop plaques and tangles.

“A major goal of the next generation of AD therapies is to identify disease-modifying compounds rather than simply treating the disease symptoms,” the authors say. “In this regard, AF267B clearly meets this criterion.”

The researchers found that an antagonist of the M1 receptors slowed learning and impaired retrieval in a mouse model of AD (3xTg-AD mice). However, AF276B rescued this deficit. AF276B also reduced levels of amyloid-beta peptide — the main constituent of amyloid plaques — and the M1 receptor antagonist increased it. The results suggest, they say, that AF276B reduces these levels by shifting the processing of amyloid-beta peptide precursor from a pathway leading to amyloid-beta peptide formation to one that precludes it.

The researchers also found that AF267B reduces the hyperphosphorylated aggregates of tau protein (which make up neurofibrillary tangles) by reducing phosphorylation by the tau kinase GSK3b. The M1 receptor agonist, on the other hand, enhanced this phosphorylation, they found.

“The improved cognitive function is closely linked with the reduction of the amyloid-beta and tau pathology in this model. We observed a reduction in these two pathological hallmarks in the hippocampus and cortex, and this is associated with improved cognitive performance in a hippocampal-dependent task. … Further work, including clinical trials in humans, will be necessary to determine if this new generation of M1 agonists will produce a similar therapeutic efficacy as was observed in the 3xTg-AD mice,” they add.