A new study identifies molecules that can be used to selectively reduce generation of the sticky, neuron-damaging plaques that are the hallmark of the Alzheimer's disease (AD) brain. The research, published by Cell Press in the September 9 issue of the journal Neuron, may lead to the development of effective and safe therapeutics for this currently incurable disease.

Previous research has suggested that an alteration in brain levels of amyloid ? proteins (A?) plays a major pathogenic role in AD, a devastating neurodegenerative disorder that causes progressive cognitive impairment and memory loss. AD is characterized by abnormal levels of A? that accumulate in the brain and form plaques that are toxic to neurons.

"A? peptides are generated when enzymes called gamma secretases snip a large protein called amyloid precursor protein (APP) into smaller pieces," explains senior study author, Dr. Steven L. Wagner from the University of California, San Diego. "Early approaches to therapeutic intervention focused on lowering total A? peptide production by using gamma secretase inhibitors (GSIs). However, this often led to adverse effects because gamma secretases are required for other key cellular activities."

Dr. Wagner and colleagues developed a screen to identify compounds (called gamma secretase modulators) that would preferentially reduce levels of the harmful A? protein without interfering with the other necessary gamma secretase functions. They identified and characterized a class of aminothiazole gamma secretase modulators (AGSMs) that selectively reduced generation of harmful A??proteins and displayed unique pharmacological properties when compared with the GSIs that are currently being used in AD clinical trials.

Dr. Wagner's group then tested the most potent orally available AGSM compound in a mouse model of AD and found that the drug significantly lowered the amount of pathological A? proteins, reduced plaque density in the brains of the treated mice and did not exhibit the toxicity associated with standard GSI treatment.

The compounds discovered in this study are unique in that they do not just globally inhibit gamma secretases but instead interact with the enzymes to selectively modulate activity, sparing the necessary enzyme functions.

"Gamma secretase is an excellent target for Alzheimer's drug discovery; however, it is also a vital enzyme with many different roles in the body. Thus, you cannot hit with a sledgehammer, but must, instead, gently tweak its activity to regulate its effects on amyloid beta protein while allowing it to carry out its many other functions," adds study coauthor, Dr. Rudolph E. Tanzi, from Massachusetts General Hospital. "The gamma secretase modulators we describe in this study do just that and thus represent a potentially valuable class of drug for the treatment and prevention of Alzheimer's disease".

The researchers are optimistic about how AGSMs might improve treatment strategies for AD. "Hopefully these types of molecules will ultimately be shown to be safe and effective in further preclinical studies and in humans," concludes Dr. Wagner. "If that turns out to be the case, they may someday in the future be used for inhibiting or even preventing AD in a manner similar to how cholesterol lowering drugs are used to treat cardiovascular diseases today."