Differential deposition of IDE and NEP in sporadic and familial Alzheimer´s disease brain

VB. DORFMAN; PASQUINI L.; RIUDAVETS M.; LÓPEZ-COSTA JJ.; VILLEGAS A.; TRONCOSO JC.; LOPERA F.; CASTAÑO EM.; MORELLI L.

NEUROBIOLOGY OF AGING

ELSEVIER SCIENCE INC

Lugar: Holanda; Año: 2010 vol. 31 p. 1743 - 1757

0197-4580

Alzheimer´s disease (AD) is characterized by amiloid ß (Aß) accumulation in the brain and is classified as familial early onset (FAD) or sporadic late-onset (SAD). Evidence suggest that deficits in the brain expression of insulin degrading enzyme (IDE) and neprilysin (NEP), both proteases involved in amyloid degradation, may promote Aß deposition in SAD. We studied by immunohistochemistry IDE and NEP cortical expression in SAD and FAD samples carrying the E280A presenilin-1 missense mutation. We showed that IDE, a soluble peptidase, is linked with aggregated Aß40 isoform while NEP, a membrane-bound protease, negatively correlates with amyloid angiopathy and its expression in the senile plaques is independent of aggregated amyloid and restricted to SAD cases. NEP, but not IDE, is over-expressed in distrophic neurites, both proteases are imunoreactive in activated astrocytes but not in microglia and IDE was the only one detected in astrocytes of white matter from FAD. The striking differences observed in the number of IDE positive plques between FAD and SAD cases support the notion that gross conformational changes involved in the modification from ¨soluble¨ active to ¨aggregated-inastive¨ IDE may be a relevant pathogenic mechanism in SAD.