Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain abeta levels.
OBJECTIVE
Active and passive immunization methodologies against amyloid-beta (Abeta) are employed to clear and reduce cerebral Abetatowards treatment of Alzheimer's disease (AD) patients. The therapeutic potential of these antibodies in AD patients is limited because of adverse inflammatory reactions and cerebral hemorrhage, which are associated with the treatment. We propose a novel approach to inhibit Abeta production via antibodies against the beta-secretase cleavage site of the amyloid precursor protein (APP). Such an approach limits APP processing by beta-secretase, mainly through the endocytic pathway, and overcomes some of the limitations of BACE inhibition. Anti-APP beta-site antibodies, tested in a cellular model expressing wild-type APP, were found to bind full-length APP, internalize into the cells and interfere with BACE activity, inhibiting both intra- and extracellular Abeta peptide formation.


METHODS
We investigated the effect of anti-beta-site antibodies in an AD animal model regarding antibody efficacy, as well as possible adverse effects in the brain and periphery that may result from antibody treatment.


CONCLUSIONS
Here, we show that long-term systemic administration of anti-APP beta-site antibodies to Tg2576 transgenic mice improved mouse cognitive functions associated with a reduction in both brain inflammation and the incidence of microhemorrhage. Furthermore, antibody treatment did not induce any peripheral autoimmunity responses. In spite of the beneficial effects observed in antibody-treated mice, brain Abeta levels were not altered as a result of antibody treatment.
Rakover
Idan
I
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel.
Arbel
Michal
M
Solomon
Beka
B
D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020300:Intracranial Hemorrhages / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D013995:Time; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D053829:Amyloid Precursor Protein Secretases