Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease

• Published in: Neurobiology of aging 2010-10, Vol.31 (10), p.1743-1757
• Main Authors: Dorfman, Verónica Berta, Pasquini, Laura, Riudavets, Miguel, López-Costa, Juan José, Villegas, Andrés, Troncoso, Juan Carlos, Lopera, Francisco, Castaño, Eduardo Miguel, Morelli, Laura
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid β; Astrocytes; Astrocytes - enzymology; Biological and medical sciences; Cerebral Amyloid Angiopathy - enzymology; Cerebral Cortex - enzymology; Cerebral Cortex - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development. Senescence. Regeneration. Transplantation; Female; Fundamental and applied biological sciences. Psychology; Human brain; Humans; Insulin degrading enzyme; Insulysin - chemistry; Insulysin - metabolism; Internal Medicine; Male; Medical sciences; Microglia - enzymology; Middle Aged; Neprilysin; Neprilysin - chemistry; Neprilysin - metabolism; Neurology; Peptide Fragments - metabolism; Plaque, Amyloid - enzymology; Presenilin; Presenilin-1 - analysis; Presenilin-1 - genetics; Protein Conformation; Vertebrates: nervous system and sense organs
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2008.09.016

Abstract Alzheimer's disease (AD) is characterized by amyloid β (Aβ) accumulation in the brain and is classified as familial early-onset (FAD) or sporadic late-onset (SAD). Evidences suggest that deficits in the brain expression of insulin degrading enzyme (IDE) and neprilysin (NEP), both proteases involved in amyloid degradation, may promote Aβ 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 Aβ40 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 dystrophic neurites, both proteases are immunoreactive in activated astrocytes but not in microglia and IDE was the only one detected in astrocytes of white matter from FAD cases. Collectively, our results support the notion that gross conformational changes involved in the modification from “natively folded-active” to “aggregated-inactive” IDE and NEP may be a relevant pathogenic mechanism in SAD.