Evidence That Aβ42 Plasma Levels in Presenilin-1 Mutation Carriers Do not Allow for Prediction of Their Clinical Phenotype

doi:10.1006/nbdi.1999.0247

Neurobiology of Disease

Volume 6, Issue 4, August 1999, Pages 280-287

https://doi.org/10.1006/nbdi.1999.0247 Get rights and content

Abstract

Mutations in the presenilin 1 (PSEN1) gene are an important cause of autosomal dominant Alzheimer's disease (AD). Both in vitro and in vivo experiments showed that PSEN1 mutations increase secretion of amyloid β42 (Aβ42), the longer and more fibrillogenic isoform of Aβ. We measured secreted Aβ42 in plasma of patients, presymptomatic mutation carriers, and escapees of two extended Belgian early-onset AD families, AD/A and AD/B, with a similar severe phenotype in terms of onset age (mean 35 years), duration of the disease (mean 6.5 years), and pathology. Both families segregate a different missense mutation in PSEN1 located in different parts of the protein: I143T in family AD/A and G384A in family AD/B. A significant increase in Aβ42 concentrations was observed in plasma of mutation carriers in family AD/B, but not in family AD/A. A differential effect of the two PSEN1 mutations on Aβ42 secretion was also detected in conditioned medium of stably transfected HEK293 cells. Both mutations increased Aβ42 secretion significantly; however, the increase was highest for G384A (5.5-fold over wild-type PSEN1), the largest effect observed for missense PSEN1 mutations to date. Although the Aβ42 concentrations measured in vivo and in vitro did not correlate with onset age, a positive correlation was obtained with age in the presymptomatic mutation carriers and a negative correlation with duration of disease in the patients. Our data obtained for PSEN1 mutation carriers suggest that measuring Aβ42 concentrations in plasma will be informative as a diagnostic marker in a limited number of cases.

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With the high sensitivity method, the Aβ1-42 ELISA had a measurement range of 7.81 to 1,000 pg/mL, and the sensitivity was 5.00 pg/mL. The CV values for interassay and intra-assay measurements were <10% and <5%, respectively [12]. In a second study, the potential disease-modifying effects of donepezil, a cholinesterase inhibitor, were evaluated by quantifying the levels of Aβ in plasma.
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Patients with the M146V mutation showed mild cortical vacuolar changes, E280A mutation caused prominent vacuolation of the neuropil and severe gliosis, and A260V mutation was associated with silver- and ubiquitin-positive inclusions resembling Pick bodies in the neurons of the dentate gyrus.42,49,70,81 Initial studies indicated that families with PS-1 mutations had increased levels of Aβ42(43) but not Aβ40, in plasma and in medium conditioned by skin fibroblasts.14,82 The increase in plasma Aβ42(43) was present even in presymptomatic subjects.
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Regular ArticleEvidence That Aβ42 Plasma Levels in Presenilin-1 Mutation Carriers Do not Allow for Prediction of Their Clinical Phenotype

Abstract

Neuron

Neurobiol. Dis.

J. Biol. Chem.

Exp. Neurol.

Neurosci. Lett.

Neuron

Cell

Neurodegeneration

Neuron

Am. J. Hum. Genet.

Neurosci. Lett.

Lancet

J. Biol. Chem.

Nat. Genet.

Cerebrospinal fluid β-amyloid(1–42) in Alzheimer's disease: Differences between early- and late-onset AD and stability during the course of disease

Arch. Neurol.

Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice

Nat. Med.

Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3

Hum. Mol. Genet.

Presenilin mutations in Alzheimer's disease

Hum. Mut.

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease

Hum. Mol. Genet.

Regular Article
Evidence That Aβ42 Plasma Levels in Presenilin-1 Mutation Carriers Do not Allow for Prediction of Their Clinical Phenotype

Cerebrospinal fluid β-amyloid_(1–42) in Alzheimer's disease: Differences between early- and late-onset AD and stability during the course of disease