The combined belt-and-suspenders approach is renowned for protecting against public humiliation, but it may hold up just as well when used in medicine. Combinations of drugs are now used in a wide variety of ways, including battling cancer, stopping human immunodeficiency virus, and they may eventually find their way into the Alzheimer disease clinic as well. In this month’s Molecular Neurodegeneration, researchers led by Brian Bacskai at Massachusetts General Hospital report that γ-secretase inhibitors, which block the enzyme that snips amyloid-β (Aβ) from its precursor, effectively reduce the buildup of Aβ in the brain, but can’t remove established amyloid plaques and heal adjacent damaged neurons—at least in mouse models of the disease. The finding strengthens previous data suggesting that γ-secretase inhibitors, if approved for use in humans, may offer the best protection when supported by other therapies that drive existing plaques from the brain.
Bacskai and colleagues used transcranial multiphoton microscopy to examine the effects of LY-411575, one of Eli Lilly’s experimental γ-secretase inhibitors, on plaques in 10-month-old APPSwe/PS1ΔE9 transgenic mice. The advantage of their method is that the same plaques can be located and studied each time the animals are put under the microscope. Joint first authors Monica Carcia-Alloza, Meenakshi Subramanian, and colleagues administered the inhibitor to the mice for three weeks but found no effect on the size of existing plaques during that time. They also found no change in the distorted, “curvy-looking” neurites in the vicinity of plaques (see ARF related news story on Meyer-Luehmann et al., 2008), suggesting that the inhibitor does not address their toxicity. They did find that the inhibitor significantly reduced levels of soluble Aβ40/42 in plasma and in the brain, and to a lesser extent the accumulation of acid-insoluble Aβ. “Together, these data suggest that although γ-secretase inhibition can successfully reduce Aβ production and aggregation, these compounds have a limited effect on reversing or clearing Aβ deposits,” write the authors. Confirming one aspect of this work, a recent human study found that a different γ-secretase inhibitor reduced production of Aβ in CSF (Bateman et al., 2009). That study did not report brain Aβ levels as measured by amyloid imaging.
The authors recognize that three weeks is a relatively short time and that a longer treatment might eventually loosen existing plaques from the brain—more work will be needed to address that possibility. It is worth noting, however, that in previous mouse experiments, pre-existing plaque burden remained unchanged even six months after production of Aβ was shut down, suggesting that spontaneous plaque degradation is nonexistent or at least inefficient (see ARF related news story). Combinations of therapies that suppress Aβ production, increase clearance of existing plaques, and reduce the toxic effects of the peptide might “provide a more successful approach to treat the illness,” write the authors.—Tom Fagan
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- Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 2008 Feb 7;451(7179):720-4. PubMed.
- Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009 Jul;66(1):48-54. PubMed.
- Garcia-Alloza M, Subramanian M, Thyssen D, Borrelli LA, Fauq A, Das P, Golde TE, Hyman BT, Bacskai BJ. Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575. Mol Neurodegener. 2009;4:19. PubMed.