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The Journal of Neuroscience, October 3, 2007, 27(40):10849-10859; doi:10.1523/JNEUROSCI.2152-07.2007

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Neurobiology of Disease
Moderate Reduction of -Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities

Tong Li,¹ Hongjin Wen,¹ Cory Brayton,⁴ Fiona M. Laird,¹ Guojun Ma,¹ Shiwen Peng,¹ Lisa Placanica,⁵ T. C. Wu,¹ Barbara J. Crain,¹ Donald L. Price,^1,2,3 Charles G. Eberhart,¹ and Philip C. Wong^1,2

Departments of ¹Pathology, ²Neuroscience, ³Neurology, and ⁴Comparative Medicine, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, and ⁵Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Correspondence should be addressed to Philip C. Wong and Tong Li, Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. Email: wong{at}jhmi.edu, Email: tli1{at}jhmi.edu

Although -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 -secretase (levels ranging from 25 to 64% of control mice). Here, we document that even 30% reduction of -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 -secretase dosage-dependent manner. Importantly, we demonstrate that there exists a critical -secretase level that reduces the risk of amyloidosis in the CNS and limits tumorigenesis in epithelia. Our findings suggest that moderate inhibition of -secretase represents an attractive anti-amyloid therapy for Alzheimer's disease.

Key words: -secretase; Alzheimer's disease; Aßamyloidosis; Notch; squamous cell carcinoma; splenomegaly

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Received May 10, 2007; revised July 24, 2007; accepted Aug. 15, 2007.

Correspondence should be addressed to Philip C. Wong and Tong Li, Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. Email: wong{at}jhmi.edu, Email: tli1{at}jhmi.edu

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Moderate Reduction of -Secretase: Is There a Therapeutic Sweet Spot?

Se Hoon Choi and Eric Norstrom
J. Neurosci. 2007 27: 13579-13580. [Full Text]  

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