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Cook JJ, Wildsmith KR, Gilberto DB, Holahan MA, Kinney GG, Mathers PD, Michener MS, Price EA, Shearman MS, Simon AJ, Wang JX, Wu G, Yarasheski KE, Bateman RJ. Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound. J Neurosci. 2010 May 12;30(19):6743-50. PubMed.
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University of Gothenburg
This is exactly what we saw in humans treated with GSI as reported in our recent Alzheimer's Research & Therapy paper (Portelius et al., 2010). Similar results have also been seen in cell lines (Portelius et al., 2009), mice (Portelius et al., 2009), and dogs (Portelius et al., Journal of Alzheimer's Disease, 2010, in press) treated with GSIs. The results speak strongly for a third APP processing pathway involving concerted β- and α-cleavages on the same APP molecule, and that this pathway is upregulated in response to γ-secretase inhibition. When seeing the increases in Aβ1-14, 1-15, and 1-16, it may be comforting to remember that these molecules do not appear to be synaptotoxic (Portelius et al., 2010).
References:
Portelius E, Dean RA, Gustavsson MK, Andreasson U, Zetterberg H, Siemers E, Blennow K. A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimers Res Ther. 2010;2(2):7. PubMed.
Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon AJ, Blennow K. A novel pathway for amyloid precursor protein processing. Neurobiol Aging. 2011 Jun;32(6):1090-8. PubMed.
Portelius E, Zhang B, Gustavsson MK, Brinkmalm G, Westman-Brinkmalm A, Zetterberg H, Lee VM, Trojanowski JQ, Blennow K. Effects of gamma-secretase inhibition on the amyloid beta isoform pattern in a mouse model of Alzheimer's disease. Neurodegener Dis. 2009;6(5-6):258-62. PubMed.
Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, Hansson O, Harmsen A, Gustavsson MK, Hanse E, Galasko D, Hampel H, Blennow K, Zetterberg H. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010;5:2. PubMed.
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