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J. Biol. Chem., Vol. 279, Issue 53, 56004-56013, December 31, 2004

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Insulin-degrading Enzyme in Brain Microvessels

PROTEOLYSIS OF AMYLOID VASCULOTROPIC VARIANTS AND REDUCED ACTIVITY IN CEREBRAL AMYLOID ANGIOPATHY^*

Laura Morelli, Ramiro E. Llovera, Irina Mathov, Lih-Fen Lue, Blas Frangione¶, Jorge Ghiso¶, and Eduardo M. Castaño||

From the Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Consejo Nacional de Investigaciones Científicas y Técnicas, Cátedra de Química Biológica Patológica, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, C1113AAD, Buenos Aires, Argentina, the Sun Health Research Institute, Sun City, Arizona 85351, and the ^¶Departments of Pathology and Psychiatry, New York University School of Medicine, New York, New York 10016

The accumulation of amyloid (A) in the walls of small vessels in the cerebral cortex is associated with diseases characterized by dementia or stroke. These include Alzheimer's disease, Down syndrome, and sporadic and hereditary cerebral amyloid angiopathies (CAAs) related to mutations within the A sequence. A higher tendency of A to aggregate, a defective clearance to the systemic circulation, and insufficient proteolytic removal have been proposed as mechanisms that lead to A accumulation in the brain. By using immunoprecipitation and mass spectrometry, we show that insulin-degrading enzyme (IDE) from isolated human brain microvessels was capable of degrading ¹²⁵I-insulin and cleaved A-(1-40) wild type and the genetic variants A A21G (Flemish), A E22Q (Dutch), and A E22K (Italian) at the predicted sites. In microvessels from Alzheimer's disease cases with CAA, IDE protein levels showed a 44% increase as determined by sandwich enzyme-linked immunosorbent assay and Western blot. However, the activity of IDE upon radiolabeled insulin was significantly reduced in CAA as compared with age-matched controls. These results support the notion that a defect in A proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature. Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular A amyloidoses.

Received for publication, June 29, 2004 , and in revised form, September 21, 2004.

^* This work was supported by a grant from the Alzheimer's Association, Agencia Nacional de Promoción Científica y Tecnológica Grant 05-10599, and National Institutes of Health Grants AG10491, AG08721, NS38777, and AG05891. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 54-11-4-964-8288; Fax: 54-11-4-962-5457; E-mail: edcast{at}ffyb.uba.ar.

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