RGD Reference Report - Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain abeta levels.

General

Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain abeta levels.
Authors:	Rakover, I Arbel, M Solomon, B
Citation:	Rakover I, etal., Neurodegener Dis. 2007;4(5):392-402. Epub 2007 May 25.
RGD ID:	10054262
Pubmed:	PMID:17536186 (View Abstract at PubMed)
DOI:	DOI:10.1159/000103250 (Journal Full-text)
BACKGROUND/OBJECTIVES: 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. RESULTS/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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
cognitive disorder		IDA		10054262		RGD
cognitive disorder		ISO	APP (Homo sapiens)	10054262; 10054262		RGD

Objects Annotated

Genes (Rattus norvegicus)

App (amyloid beta precursor protein)

Genes (Mus musculus)

App (amyloid beta precursor protein)

Genes (Homo sapiens)

APP (amyloid beta precursor protein)

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Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain abeta levels.