Prevention of Alzheimer’s disease by control of beta-amyloid production in the periphery
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Abstract
Abstract
Using a novel approach for identification of disease modifier genes, it was demonstrated that the level of expression of the Presenilin2 gene by the liver regulates the accumulation of pathogenic concentrations of Alzheimer’s disease (AD)-initiating beta-amyloid within the brain. The anti-leukemia therapeutic imatinib (trade name Gleevec), which does not cross the blood-brain barrier, reduced liver production of beta-amyloid and lowered its accumulation in the brain below pathogenic levels. These observations suggest that Alzheimer’s disease is preventable. The imatinib-related compound, imatinib para-diaminomethylbenzene trihydrochloride, is more than three-fold more potent in inhibiting beta-amyloid production than imatinib and exhibits only 1/16th of the activity of imatinib in the inhibition of Abl kinase (the imatinib target in leukemia), resulting in a selectivity ratio of nearly 60 for the AD indication. These studies suggest that prophylactic reduction of beta-amyloid at the site of its production in the livers of aging humans has the potential to lower the incidence AD and point to the identity of a drug that can accomplish that goal.
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References
Barten DM, Albright CF Therapeutic strategies for Alzheimer's disease. Mol Neurobiol 2008; 37:171-186. DOI: 10.1007/s12035-008-8031-2
Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012; 367(9):795-804. doi: 10.1056/NEJMoa1202753
Cancino GI, Toledo EM, Leal NR, et al. STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits. Brain 2008; 131: 2425-2442. DOI: 10.1093/brain/awn125
Eisele YS, Fritschi SK, Hamaguchi T, et al. Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J Neurosci 2014; 34:10264-10273. DOI: 10.1523/JNEUROSCI.1608-14.2014
Fagan AM, Xiong C, Jasielec MS, et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci Transl Med 2014; 6(226):226ra30. doi: 10.1126/scitranslmed.3007901
He G, Luo W, Li P, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 2010; 467: 95-99. DOI: 10.1038/nature09325
Head E, Doran E, Nistor M, et al. Plasma Aβ as a Function of Age, Level of Intellectual Disability and Presence of Dementia in Down syndrome. J Alzheimer’s Disease 2011; 23(3):399-409. doi:10.3233/JAD-2010-101335
Hock BJ, Lattal KM, Kulnane LS, et al. Pathology associated memory deficits in Swedish mutant genome-based amyloid precursor protein transgenic mice. Curr Aging Sci 2009; 2, 205-13.
Kulnane LS, Lamb BT Neuropathological characterization of mutant amyloid precursor protein yeast artificial chromosome transgenic mice. Neurobiol Dis 2001; 8: 982-992. DOI: 10.1006/nbdi.2001.0446
Lehman EJ, Kulnane LS, Gao Y, et al. Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse. Hum Mol Genet 2003; 12: 2949-2956. DOI: 10.1093/hmg/ddg322
Ryman D, Gao Y, Lamb BT Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease. Neurobiol Aging 2008; 29: 1190-1198. DOI: 10.1016/j.neurobiolaging.2007.02.017
Selkoe DJ Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001; 81: 741-766. PubMed ID: 11274343
Stabler SM, Ostrowski LL, Janicki SM, Monteiro MJ A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein. J Cell Biol 1999; 145: 1277-1292. DOI: 10.1083/jcb.145.6.1277
Sutcliffe JG, Hedlund PB, Thomas EA, et al. Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease. J Neurosci Res 2011; 89:808-814. DOI: 10.1002/jnr.22603
Sutcliffe JG, Hilbush BS Compositions and Methods for Reduction of Amyloid-Beta Load. 2016 European Patent No. 2776035.
Sutcliffe JG, Hilbush BS, Bloom FE Modification of Amyloid-Beta Load in Non-Brain Tissue. 2015 European Patent No. 2365804.
Tanzi RE Molecular genetics of Alzheimer's disease and the amyloid beta peptide precursor gene. Ann Med 1989; 21: 91-94. DOI: 10.3109/07853898909149191
Terry RD Alzheimer's disease and the aging brain. J Geriatr Psychiatry Neurol 2006; 19: 125-128. DOI: 10.1177/0891988706291079
Waring SC, Rosenberg RN Genome-wide association studies in Alzheimer disease. Arch Neurol 2008; 65: 329-334. DOI: 10.1001/archneur.65.3.329
Weintraub MK, Bisson CM, Nouri JN, et al. Imatinib methanesulfonate reduces hippocampal amyloid-β and restores cognitive function following repeated endotoxin exposure. Brain Behav Immun 2013; 33:24-28. DOI: 10.1016/j.bbi.2013.05.002
Wolfe MS. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry 2006; 45: 7931-7939. DOI: 10.1021/bi060799c
Zigman WB, Lott IT Alzheimer’s disease in Down syndrome: neurobiology and risk. Mental Retard Dev Disabilities Res Rev 2007;13: 237–246. DOI: 10.1002/mrdd.20163