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A Better Gamma-Secretase Inhibitor for the Treatment of Alzheimer's Disease

Gamma-secretase inhibitors block the formation of the amyloid-β associated with Alzheimer's disease, but to date they are just one more in a long line of failed attempts to produce a therapy for that condition by adjusting the operation of cellular metabolism in the disease state in some way. Existing pharmaceutical gamma-secretase inhibitors act too generally, causing significant disruption of essential mechanisms that far outweighs whatever benefit they might produce. Here, however, researchers claim to have established a much more specific gamma-secretase inhibitor, one that only disrupts the formation of amyloid-β and nothing else. Is this good enough to justify another run at this challenge? Time will tell.

The most common neurodegenerative disorder, Alzheimer's disease is characterized by the buildup of amyloid plaques and neurofibrillary tangles in several brain regions. The leading hypothesis for its pathogenesis is the amyloid cascade - which suggests that the amyloid beta-protein, and particularly the amyloid-beta 42 peptide, initiates the disease process. An imbalance between the production and clearance of amyloid-beta results in the protein's aggregation into larger plaques that lead to the death of brain cells and the cognitive symptoms seen in Alzheimer patients. Several potential treatments have been developed that specifically target amyloid, but none have been effective in halting disease progression.

Amyloid-beta is produced by the cleavage of the larger amyloid precursor protein (APP) by an enzyme called gamma-secretase. Previous research led to the development of gamma-secretase inhibitors that totally block the function of the enzyme, but in clinical trials these drugs produced serious side effects through their effects on the processing of other proteins. As an alternative, researchers first developed the concept of gamma-secretase modulators (GSMs), which change but do not totally suppress the enzyme's activity, back in 2000. More recently reseearchers developed a group of soluble GSMs, one of which - SGSM-36 - appeared to be a promising candidate for clinical development.

In the current study, the researchers showed that three days of treatment with SGSM-36 reduced levels of amyloid-beta 42 in the brains and plasma of a validated mouse model of inherited Alzheimer's without affecting the processing of APP by other enzymes. In cellular models they compared the action of SGSM-36 to that of semagacestat, one of the gamma-secretase inhibitors that failed in clinical trials. While SGSM-36 treatment only reduced levels of the toxic amyloid-beta 40 and 42 peptides, semagacestat reduced all form of amyloid as well as gamma-secretase processing of other proteins, including the important signaling protein Notch, reduction of which may have caused the toxic effects of gamma-secretase inhibitor treatment.

"Genetic, biochemical, molecular biological and pathological evidence all support the hypothesis that excessive accumulation of amyloid-beta - particularly amyloid-beta 42 - is the primary event leading to Alzheimer's related pathology. In our future studies, we will be testing SGSM-36 against similar molecules that may have equal or higher potency in reducing amyloid-beta 42 and further investigating its molecular mechanisms in animal models, with the eventual goal of testing its potential in clinical trials."

Link: http://www.massgeneral.org/about/pressrelease.aspx?id=2161

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