A New Direction for Treating Alzheimer Disease

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A New Direction for Treating Alzheimer Disease

Selective M1 cholinergic agonists show promise as a novel approach to treating Alzheimer disease.

The overall goal of this study was to evaluate the molecular and behavioral consequences of modulating the M1 muscarinic receptor in a mouse model that mimics Alzheimer disease (AD). The researchers’ rationale came from prior reports that selective stimulation of this receptor in cultured cells altered processing of the amyloid precursor protein by reducing levels of the toxic amyloid-ß42 (Aß42) fragment. Two pharmacologic treatments — the selective M1 agonist AF267B and the M1 antagonist dicyclomine — were tested on triple-transgenic mutant mice that progressively develop many of the pathologic features of AD, including amyloid plaques, neuronal tau aggregates, cholinergic dysfunction, and cognitive impairments.

The investigators found that, compared to treatment with an inert vehicle, AF267B treatment decreased Aß42 levels in the brain and the number of amyloid plaques in the hippocampus and cortex (but not in the amygdala), whereas dicyclomine treatment increased plaque counts in these three areas. The two treatments had similar inverse effects on tau pathology: AF267B treatment decreased — and dicyclomine increased — tau phosphorylation and tau immunoreactive staining in the brain. AF267B treatment improved performance in the Morris water maze memory test (which depends on the hippocampus) but did not affect avoidance behavior (which depends on the amygdala), whereas dicyclomine treatment worsened performance on both tests.

Comment: Researchers focusing on AD therapies are aiming to identify and develop compounds that alter the disease process — not simply treat AD symptoms. In this study using an animal model of AD, the selective M1 agonist AF267B effectively reduced the two major neuropathologic hallmarks of AD and rescued memory deficits. This major finding supports the view that selective stimulation of the M1 muscarinic receptor enhances ß-secretase activity, thereby reducing the production of Aß42 fragments that are implicated in AD. Thus, selective M1 agonists, such as AF267B in the current study, show promise. AF267B reversed the amyloid plaques, tau pathology, and cognitive deficits in an AD transgenic-mouse model; whether it would have similar effects in humans with AD remains unknown, but it should be tested.

— John H. Growdon, MD

Dr. Growdon is Professor of Neurology, Harvard Medical School and Department of Neurology, Massachusetts General Hospital, Boston.

Published in Journal Watch Neurology August 22, 2006