Dataset Information

The pathogenic a?43 is enriched in familial and sporadic Alzheimer disease.

ABSTRACT: The amyloid-cascade hypothesis posits that the role of amyloid ?-peptide (A?) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of A? are produced, of which the 40 and 42 residue variants (A?40 and A?42) are the most common. A?42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer A? isoforms, like the less studied A?43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate A?43 in AD, we conducted a quantitative study on A?43 levels in human brain. We homogenized human brain tissue and prepared fractions of various solubility; tris buffered saline (TBS), sodium dodecyl sulfate (SDS) and formic acid (FA). Levels of A?43, as well as A?40 and A?42, were quantified using ELISA. We compared quantitative data showing A? levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed A?43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases. A?42 and A?43 were enriched in the less soluble fractions (SDS and FA) of SAD and FAD cases in both occipital and frontal cortex. Thus, although the total levels of A?43 in human brain are low compared to A?40 and A?42, we suggest that A?43 could initiate the formation of oligomers and amyloid plaques and thereby be crucial to AD pathogenesis.

SUBMITTER: Sandebring A

PROVIDER: S-EPMC3569467 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The pathogenic aβ43 is enriched in familial and sporadic Alzheimer disease.

Sandebring Anna A Welander Hedvig H Winblad Bengt B Graff Caroline C Tjernberg Lars O LO

PloS one 20130211 2

The amyloid-cascade hypothesis posits that the role of amyloid β-peptide (Aβ) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of Aβ are produced, of which the 40 and 42 residue variants (Aβ40 and Aβ42) are the most common. Aβ42 has a strong tendency to form neurotoxic aggregates and is involved in AD path ...[more]

PMID: 23409063

Similar Datasets

Project description:BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Dataset Information

The pathogenic a?43 is enriched in familial and sporadic Alzheimer disease.

Publications

The pathogenic aβ43 is enriched in familial and sporadic Alzheimer disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets