Modeling an anti-amyloid combination therapy for Alzheimer's disease.

Abstract

As only symptomatic treatments are now available for Alzheimer's disease (AD), safe and effective mechanism-based therapies remain a great unmet need for patients with this neurodegenerative disease. Although gamma-secretase and BACE1 [beta-site beta-amyloid (Abeta) precursor protein (APP) cleaving enzyme 1] are well-recognized therapeutic targets for AD, untoward side effects associated with strong inhibition or reductions in amounts of these aspartyl proteases have raised concerns regarding their therapeutic potential. Although moderate decreases of either gamma-secretase or BACE1 are not associated with mechanism-based toxicities, they provide only modest benefits in reducing Abeta in the brains of APPswe/PS1DeltaE9 mice. Because the processing of APP to generate Abeta requires both gamma-secretase and BACE1, it is possible that moderate reductions of both enzymes would provide additive and significant protection against Abeta amyloidosis. Here, we test this hypothesis and assess the value of this novel anti-amyloid combination therapy in mutant mice. We demonstrate that genetic reductions of both BACE1 and gamma-secretase additively attenuate the amyloid burden and ameliorate cognitive deficits occurring in aged APPswe/PS1DeltaE9 animals. No evidence of mechanism-based toxicities was associated with such decreases in amounts of both enzymes. Thus, we propose that targeting both gamma-secretase and BACE1 may be an effective and safe treatment strategy for AD.

• Authors: Vivian W Chow, Alena V Savonenko, Tatiana Melnikova, Hyunsu Kim, Donald L Price, Tong Li, Philip C Wong
• Journal: Science translational medicine (Sci Transl Med) Vol. 2 Issue 13 Pg. 13ra1 (Jan 06 2010) ISSN: 1946-6242 [Electronic] United States
• PMID: 20371462 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Alzheimer Disease (therapy)
• Amyloid (antagonists & inhibitors, chemistry)
• Amyloid Precursor Protein Secretases (genetics)
• Animals
• Aspartic Acid Endopeptidases (genetics)
• Behavior, Animal
• Combined Modality Therapy (methods)
• Genotype
• Humans
• Maze Learning
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Animal
• Models, Genetic
• Mutation