Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease
Jessica F Jordão, Carlos A Ayala-Grosso, Kelly Markham, Yuexi Huang, Rajiv Chopra, JoAnne McLaurin, Kullervo Hynynen, Isabelle Aubert, Jessica F Jordão, Carlos A Ayala-Grosso, Kelly Markham, Yuexi Huang, Rajiv Chopra, JoAnne McLaurin, Kullervo Hynynen, Isabelle Aubert
Abstract
Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Abeta), which circulate in the bloodstream and remove Abeta from the brain. In mouse models of AD, the administration of anti-Abeta antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Abeta plaque pathology. Therefore, delivering anti-Abeta antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB), allowing intravenously administered therapeutics to enter the brain. Our goal was to establish that anti-Abeta antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) can reduce plaque pathology. To test this, TgCRND8 mice received intravenous injections of MRI and FUS contrast agents, as well as anti-Abeta antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Abeta plaques in targeted cortical areas. Four days post-treatment, Abeta pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Abeta antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer's disease. Nat Rev Immunol. 2006;6:404–416.
- Hawkes CA, McLaurin J. Immunotherapy as treatment for Alzheimer's disease. Expert Rev Neurother. 2007;7:1535–1548.
- Thakker DR, Weatherspoon MR, Harrison J, Keene TE, Lane DS, et al. Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci U S A. 2009;106:4501–4506.
- Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, et al. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci. 2002;22:6331–6335.
- Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001;220:640–646.
- Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006;103:11719–11723.
- Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem Biophys Res Commun. 2006;340:1085–1090.
- Raymond SB, Treat LH, Dewey JD, McDannold NJ, Hynynen K, et al. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. PLoS ONE. 2008;3:e2175.
- Chopra R, Curiel L, Staruch R, Morrison L, Hynynen K. An MRI-compatible system for focused ultrasound experiments in small animal models. Medical Physics. 2009;36:1867–1874.
- Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, et al. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem. 2001;276:21562–21570.
- Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–842.
- Wilcock DM, Colton CA. Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers Dis. 2008;15:555–569.
- Opar A. Mixed results for disease-modification strategies for Alzheimer's disease. Nat Rev Drug Discov. 2008;7:717–718.
- Bard F, Cannon C, Barbour R, Burke RL, Games D, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6:916–919.
- DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001;98:8850–8855.
- Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, et al. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004;1:24–34.
- Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, et al. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease. Peptides. 2002;23:2223–2226.
- Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, et al. Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci. 2003;23:3745–3751.
- Sheikov N, McDannold N, Vykhodtseva N, Jolesz F, Hynynen K. Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound Med Biol. 2004;30:979–989.
- Sheikov N, McDannold N, Sharma S, Hynynen K. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008;34:1093–1104.
- Hynynen K, McDannold N, Vykhodtseva N, Raymond S, Weissleder R, et al. Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J Neurosurg. 2006;105:445–454.
- Janus C, Welzl H, Hanna A, Lovasic L, Lane N, et al. Impaired conditioned taste aversion learning in APP transgenic mice. Neurobiol Aging. 2004;25:1213–1219.
- Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000;408:979–982.
- Dasilva KA, Brown ME, McLaurin J. Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine. Vaccine. 2009;27:1365–1376.
- McLaurin J, Cecal R, Kierstead ME, Tian X, Phinney AL, et al. Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med. 2002;8:1263–1269.
- Frenkel D, Balass M, Solomon B. N-terminal EFRH sequence of Alzheimer's beta-amyloid peptide represents the epitope of its anti-aggregating antibodies. J Neuroimmunol. 1998;88:85–90.
- McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, et al. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006;12:801–808.
- Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002;5:452–457.
- Braakman N, Matysik J, van Duinen SG, Verbeek F, Schliebs R, et al. Longitudinal assessment of Alzheimer's beta-amyloid plaque development in transgenic mice monitored by in vivo magnetic resonance microimaging. J Magn Reson Imaging. 2006;24:530–536.
Source: PubMed