title: Decreased neprilysin immunoreactivity in Alzheimer disease, but not in pathological aging.
abstract: Although evidence suggests that extensive cortical beta-amyloid (Abeta) deposition is essential in Alzheimer disease (AD), it is also detected in nondemented elderly individuals with pathologic aging (PA). Given evidence that neutral endopeptidase (NEP) or neprilysin, a key enzyme for clearance of Abeta, is decreased in AD, the goal of the present study was to determine if NEP was also decreased in PA. We measured NEP immunoreactivity in frontal cortex of 12 AD and six PA cases and compared this with 10 normal (N) elderly individuals. None had any significant other pathology, and they were similar with respect to age, sex, and postmortem delay. In addition, Abeta1-40 and Abeta1-42 were measured by enzyme-linked immunosorbent assay (ELISA), whereas tau, synaptophysin, and alpha-synuclein were measured on Western blots. The AD cases had more neuritic plaques, neurofibrillary tangles, higher Braak stage, and more tau immunoreactivity in frontal cortex than both PA and N. In contrast, both PA and AD had more senile plaques and Abeta1-42 than N. NEP immunoreactivity was decreased in AD but not in PA. The decrease was unlikely the result of neuronal or synaptic loss because NEP immunoreactivity in frontotemporal degeneration with comparable degrees of synaptic loss as the AD cases was not different from control subjects. Although NEP enzyme activity was decreased in approximately half the AD cases, on average, it was not decreased compared with N or PA. The results add further evidence that PA is distinct from AD and indicate that decreased Abeta degradation by NEP is unlikely to contribute significantly to amyloid deposition in PA or, in many cases, of AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Deng-Shun
authors.initials: DS
authors.lastname: Wang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lipton
authors.forename: Mindy J
authors.initials: MJ
authors.lastname: Katz
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Herman
authors.initials: H
authors.lastname: Buschke
authors.forename: Gail
authors.initials: G
authors.lastname: Kuslansky
authors.forename: Joe
authors.initials: J
authors.lastname: Verghese
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Chris
authors.initials: C
authors.lastname: Eckman
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D003704:Dementia / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000276:immunology / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011180:Postmortem Changes; D018709:Statistics, Nonparametric; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D015260:Neprilysin