Moderate reduction of γ-secretase attenuates amyloid burden and limits mechanism-based liabilities Journal Article
| Authors: | Li, T.; Wen, H.; Brayton, C.; Laird, F. M.; Ma, G.; Peng, S.; Placanica, L.; Wu, T. C.; Crain, B. J.; Price, D. L.; Eberhart, C. G.; Wong, P. C. |
| Article Title: | Moderate reduction of γ-secretase attenuates amyloid burden and limits mechanism-based liabilities |
| Abstract: | Although γ-secretase is recognized as a therapeutic target for Alzheimer's disease, side effects associated with strong inhibition of this aspartyl protease raised serious concerns regarding this therapeutic strategy. However, it is not known whether moderate inhibition of this enzyme will allow dissociation of beneficial effects in the CNS from mechanism-based toxicities in the periphery. We tested this possibility by using a series of mice with genetic reduction of γ-secretase (levels ranging from 25 to 64% of control mice). Here, we document that even30%reduction of γ-secretase can effectively ameliorate amyloid burden in the CNS. However, global reduction of this enzyme below a threshold level increased the risk of developing squamous cell carcinoma as well as abnormal proliferation of granulocytes in a γ-secretase dosage-dependent manner. Importantly, we demonstrate that there exists a critical γ-secretase level that reduces the risk of amyloidosis in the CNS and limits tumorigenesis in epithelia. Our findings suggest that moderate inhibition of γ-secretase represents an attractive anti-amyloid therapy for Alzheimer's disease. Copyright © 2007 Society for Neuroscience. |
| Keywords: | mutation; squamous cell carcinoma; flow cytometry; cell proliferation; animals; mice; enzyme inhibition; skin neoplasms; notch receptor; amyloidosis; age factors; mice, inbred c57bl; central nervous system; carcinogenesis; mice, transgenic; models, animal; disease model; gene expression regulation; membrane glycoproteins; splenomegaly; enzyme-linked immunosorbent assay; alzheimer disease; granulocyte; amyloid precursor protein secretases; gamma secretase; presenilin-1; behavior, animal; amyloid beta-protein; notch; alzheimer's disease; amyloid; enzyme blood level; γ-secretase; aβ amyloidosis; amyloid protein; maze learning |
| Journal Title: | The Journal of Neuroscience |
| Volume: | 27 |
| Issue: | 40 |
| ISSN: | 0270-6474 |
| Publisher: | Society for Neuroscience |
| Date Published: | 2007-10-03 |
| Start Page: | 10849 |
| End Page: | 10859 |
| Language: | English |
| DOI: | 10.1523/jneurosci.2152-07.2007 |
| PUBMED: | 17913918 |
| PROVIDER: | scopus |
| PMCID: | PMC6672827 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 23" - "Export Date: 17 November 2011" - "CODEN: JNRSD" - "Source: Scopus" |
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