Beneficial Effect of Antibodies Against β- Secretase Cleavage Site of APP on Alzheimer's-like Pathology in Triple-transgenic Mice

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Oct 17

PMID 23071606

Citations 5

Authors

Inna Rabinovich-Nikitin

Idan S Rakover

Maria Becker

Beka Solomon

Affiliations

Soon will be listed here.

Abstract

The toxicity of amyloid β and tau, the two hallmark proteins in Alzheimer's disease (AD), has been extensively studied individually. Recently new data suggest their possible interactions and synergistic effects in the disease. In this study, we investigate the ability of antibodies against the β secretase cleavage site on APP, named BBS1, to affect tau pathology, besides their well established effect on intracellular Aβ and amyloid load. For this purpose we treated the triple transgenic mice model of AD (3x Tg-AD) with mAb BBS1 intracerebroventricularly, using mini osmotic pumps for one month. The experimental data demonstrated reduction in total and phosphorylated tau levels, explained by significant reduction in GSK3β which phosphorylates tau on sites recognized by antibodies against PHF1 and AT-8. The treatment increased the cognitive capabilities and reduced the brain inflammation levels which accompany AD pathology. The data showing that tau pathology was significantly reduced by BBS1 antibodies suggest a close interaction between tau and Aβ in the development of AD, and may serve as an efficient novel immunotherapy against both hallmarks of this disease.

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References

Caccamo A, Oddo S, Tran L, LaFerla F . Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol. 2007; 170(5):1669-75. PMC: 1854961. DOI: 10.2353/ajpath.2007.061178. View

Kim H, Kim E, Lee J, Park C, Kim S, Seo J . C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression. FASEB J. 2003; 17(13):1951-3. DOI: 10.1096/fj.03-0106fje. View

Takahashi R, Milner T, Li F, Nam E, Edgar M, Yamaguchi H . Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002; 161(5):1869-79. PMC: 1850783. DOI: 10.1016/s0002-9440(10)64463-x. View

Buttini M, Masliah E, Barbour R, Grajeda H, Motter R, Johnson-Wood K . Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease. J Neurosci. 2005; 25(40):9096-101. PMC: 6725749. DOI: 10.1523/JNEUROSCI.1697-05.2005. View

Gouras G, Tsai J, Naslund J, Vincent B, Edgar M, Checler F . Intraneuronal Abeta42 accumulation in human brain. Am J Pathol. 2000; 156(1):15-20. PMC: 1868613. DOI: 10.1016/s0002-9440(10)64700-1. View

Citron M . Beta-secretase as a target for the treatment of Alzheimer's disease. J Neurosci Res. 2002; 70(3):373-9. DOI: 10.1002/jnr.10393. View

Roman G . Brain infarction and the clinical expression of Alzheimer disease. JAMA. 1997; 278(2):113-4. DOI: 10.1001/jama.1997.03550020045023. View

Muyllaert D, Kremer A, Jaworski T, Borghgraef P, Devijver H, Croes S . Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology?. Genes Brain Behav. 2008; 7 Suppl 1:57-66. DOI: 10.1111/j.1601-183X.2007.00376.x. View

McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K . Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999; 46(6):860-6. DOI: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m. View

10.

Hemming M, Elias J, Gygi S, Selkoe D . Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009; 4(12):e8477. PMC: 2793532. DOI: 10.1371/journal.pone.0008477. View

11.

Oddo S, Caccamo A, Shepherd J, Murphy M, Golde T, Kayed R . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003; 39(3):409-21. DOI: 10.1016/s0896-6273(03)00434-3. View

12.

Devi L, Ohno M . Mitochondrial dysfunction and accumulation of the β-secretase-cleaved C-terminal fragment of APP in Alzheimer's disease transgenic mice. Neurobiol Dis. 2011; 45(1):417-24. PMC: 3225635. DOI: 10.1016/j.nbd.2011.09.001. View

13.

Rakover I, Arbel M, Solomon B . Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain abeta levels. Neurodegener Dis. 2007; 4(5):392-402. DOI: 10.1159/000103250. View

14.

Citron M . Emerging Alzheimer's disease therapies: inhibition of beta-secretase. Neurobiol Aging. 2002; 23(6):1017-22. DOI: 10.1016/s0197-4580(02)00122-7. View

15.

Hoover B, Reed M, Su J, Penrod R, Kotilinek L, Grant M . Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010; 68(6):1067-81. PMC: 3026458. DOI: 10.1016/j.neuron.2010.11.030. View

16.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole G . Inflammation and Alzheimer's disease. Neurobiol Aging. 2000; 21(3):383-421. PMC: 3887148. DOI: 10.1016/s0197-4580(00)00124-x. View

17.

Gendron T, Petrucelli L . The role of tau in neurodegeneration. Mol Neurodegener. 2009; 4:13. PMC: 2663562. DOI: 10.1186/1750-1326-4-13. View

18.

King D, Arendash G . Maintained synaptophysin immunoreactivity in Tg2576 transgenic mice during aging: correlations with cognitive impairment. Brain Res. 2002; 926(1-2):58-68. DOI: 10.1016/s0006-8993(01)03294-2. View

19.

Pimplikar S, Nixon R, Robakis N, Shen J, Tsai L . Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. J Neurosci. 2010; 30(45):14946-54. PMC: 3426835. DOI: 10.1523/JNEUROSCI.4305-10.2010. View

20.

Yoon S, Choi J, Yoon J, Huh J, Kim D . BACE inhibitor reduces APP-beta-C-terminal fragment accumulation in axonal swellings of okadaic acid-induced neurodegeneration. Neurobiol Dis. 2006; 22(2):435-44. DOI: 10.1016/j.nbd.2005.12.013. View