Gamma Secretase Modulators Promising In Alzheimer's Animal Model Studies

Armen Hareyan's picture
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Gamma secretase modulators have shown promise in Alzheimer's disease animal model efficacy studies, according to research conducted by TorreyPines Therapeutics, Inc..

Presented by Steven Wagner, Ph.D., the company's Chief Scientific Officer, at the recent Keystone Symposium on Alzheimer's Disease, data demonstrated that GSMs provide a more selective mechanism than gamma secretase inhibitors (GSIs). The in vivo research involved internally discovered and optimized compounds that modulate the g-secretase complex without inhibiting its catalytic activity. These GSMs appear to reduce the formation of the longer pathogenic Ab peptides (e.g, Ab42) and allow the g-secretase enzyme complex to generate the shorter, less fibrillogenic Ab peptides such as Ab38 and Ab37 and to perform its other necessary functions.

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"We have identified a series of GSM compounds that are intended to modulate the enzyme's activity without preventing it from performing its normal functions," said Dr. Wagner. "These orally bio-available, small molecule GSMs appear to have addressed some of the pitfalls associated with the GSI compounds, which have been associated with side effects. The significance of our findings is that we may be able to selectively attenuate the pathological functions of this enzyme complex without affecting the other critical physiological functions it performs."

The major pathological hallmark of Alzheimer's disease is the abundance of deposits called neuritic plaques in key areas of the brain that control memory and cognition. These neuritic plaques are largely comprised of aggregations of fibrillar peptides referred to as amyloid b, or Ab peptides. Evidence indicates that individuals genetically predisposed to early-onset forms of Alzheimer's disease make a greater proportion of the longer Ab peptides, especially Ab42, relative to unaffected individuals. All of these Ab peptides, including the pathogenic Ab42 peptide, are derived via proteolysis from a much larger precursor molecule known as the amyloid b precursor protein (APP).

During normal catabolism, two crucial enzymes, or proteases, are responsible for generating these Ab peptides from APP. The first enzyme, beta secretase (b-secretase), cuts the APP molecule into two major pieces comprised of a soluble extracellular fragment and a membrane-associated fragment. The second enzyme, gamma secretase (g-secretase), then cleaves the membrane- associated fragment into one of several different Ab peptides that vary in length from 34 to 42 amino acids.

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