Insulin-degrading Enzyme in Brain Microvessels PROTEOLYSIS OF AMYLOID
VASCULOTROPIC VARIANTS AND REDUCED ACTIVITY IN CEREBRAL AMYLOID ANGIOPATHY

MORELLI L; LLOVERA R; MATHOV I; LUE LF; FRANGIONE B; GHISO J; CASTAÑO EM

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2004 vol. 279 p. 56004 - 56013

0021-9258

The accumulation of amyloid
(A
) in the walls ofsmall vessels in the cerebral cortex is associated withdiseases characterized by dementia or stroke. These includeAlzheimer’s disease, Down syndrome, and sporadicand hereditary cerebral amyloid angiopathies(CAAs) related to mutations within the A
sequence. Ahigher tendency of A
to aggregate, a defective clearanceto the systemic circulation, and insufficient proteolyticremoval have been proposed as mechanisms thatlead to A
accumulation in the brain. By using immunoprecipitationand mass spectrometry, we show that insulin-degrading enzyme (IDE) from isolated humanbrain microvessels was capable of degrading 125I-insulinand cleaved A
-(1–40) wild type and the genetic variantsA
A21G (Flemish), A
E22Q (Dutch), and A
E22K (Italian)at the predicted sites. In microvessels from Alzheimer’sdisease cases with CAA, IDE protein levels showeda 44% increase as determined by sandwich enzymelinkedimmunosorbent assay and Western blot. However,the activity of IDE upon radiolabeled insulin wassignificantly reduced in CAA as compared with agematchedcontrols. These results support the notion thata defect in A
proteolysis by IDE contributes to theaccumulation of this peptide in the cortical microvasculature.Moreover they raise the possibility that IDE inhibitionor inactivation is a pathogenic mechanism thatmay open novel strategies for the treatment of cerebrovascularA
amyloidoses