Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells

@article{Kovacs1996AlzheimerassociatedP1,
  title={Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells},
  author={Dora M. Kovacs and Hillary J. Fausett and Keith John Page and Tae-Wan Kim and Robert D. Moir and David E. Merriam and Richard D. Hollister and Olivia G. Hallmark and Ronald Mancini and Kevin M. Felsenstein and Bradley T. Hyman and Rudolph E. Tanzi and Wilma Wasco},
  journal={Nature Medicine},
  year={1996},
  volume={2},
  pages={224-229}
}
Mutations in two recently identified genes appear to cause the majority of early–onset familial Alzheimer's disease (FAD). These two novel genes, presenilin 1 (PS1) and presenilin 2 (PS2) are members of an evolutionarily conserved gene family. The normal biological role(s) of the presenilins and the mechanism(s) by which the FAD–associated mutations exert their effect remain unknown. Employing in situ hybridization, we demonstrate that the expression patterns of PS1 and PS2 in the brain are… Expand
Localization and Possible Functions of Presenilins in Brain
TLDR
Available evidence points to pyramidal neurons as the most logical site for pathological change in AD, where mutations in PS mutants show relative increases in the amount of A beta42/43 compared with A beta40 in plasma, fibroblasts and brain. Expand
Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease
TLDR
Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenILin FAD cases were similar to control cases and sporadic AD cases, indicating accumulation of full length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined. Expand
Expression of presenilin-1 and -2 mRNAs in rat and Alzheimer's disease brains
TLDR
The present data indicate that the PS genes may play important roles in specific neurons in normal brain, and that the decreased expression in neurons in sporadic AD brain may bear some relationship to the pathogenesis. Expand
Immunohistochemical analysis of presenilin‐1 expression in the mouse brain
TLDR
PS‐1 expression was found to be broadly distributed throughout the mouse brain, not only in structures involved in AD pathology, but also in structures unaltered by this disease. Expand
Alzheimer’s disease presenilin-1 expression modulates the assembly of neurofilaments
TLDR
Presenilin-1, neurofilament-H and tau proteins showed co-localization as evidenced by confocal microscopy, suggesting a possible physiological connection between these three proteins, and appears to influence assembly of the H subunit into neurofilaments and the subsequent formation of new neurites. Expand
Presenilin mutations in Alzheimer's disease
TLDR
The presenilins (PS‐1 and PS‐2) are 2 members of a novel family of genes encoding integral membrane proteins recently implicated in Alzheimer's disease (AD) pathology, and their high degree of homology predicts similar biological activities. Expand
The Alzheimer’s Disease-Associated Presenilins Are Differentially Phosphorylated Proteins Located Predominantly within the Endoplasmic Reticulum
TLDR
Selective phosphorylation of PS-2 proteins within the acidic domain missing in PS-1 indicates differences in the biological functions and regulation of the two highly homologous proteins. Expand
Membrane Topology of Alzheimer’s Disease-related Presenilin 1
TLDR
This study expresses a series of C-terminally deleted PS1 mutants fused to the hydrophilic portion of Escherichia coli leader peptidase in vitro using a reticulocyte lysate in the presence of microsomal membranes, and proposes a novel “seven membrane-spanning and one membrane-embedded” topological model for presenilins. Expand
Presenilins, the Endoplasmic Reticulum, and Neuronal Apoptosis in Alzheimer's Disease
TLDR
When expressed in cultured cells and transgenic mice, mutant PSs promote increased production of a long form of amyloid β‐peptide (Aβ1‐42) that may possess enhancedAmyloidogenic and neurotoxic properties. Expand
Monogenic determinants of familial Alzheimer's disease: presenilin-1 mutations
TLDR
It is shown that PS1 mutations result in elevated Aβ42/Aβ40 ratios in plasma of FAD patients, in transgenic mice and in transfected cell lines, and the mechanism by which this may affect neurodegeneration remains to be determined. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 20 REFERENCES
The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families
TLDR
This work has localized the PS-1 gene to a 75 kb region and present the structure of this gene, evidence for alternative splicing and describe six novel mutations in early onset FAD pedigrees all of which alter residues conserved in the STM26 (Presenilin 2: PS-2) gene. Expand
Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP).
TLDR
Although APLP2 cannot give rise to A beta, its near identity to APP outside the A beta domain confounds the interpretation of previous immunocytochemical and biochemical characterizations of APP biosynthesis and metabolism. Expand
Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene
TLDR
Analysis of the nucleotide sequence of the open reading frame of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50–70 years versus 30–60 years for AD3). Expand
Cellular specificity and regional distribution of amyloid beta protein precursor alternative transcripts are unaltered in Alzheimer hippocampal formation.
TLDR
In situ hybridization using biotinylated oligonucleotide probes designed to localize specific APP mRNA transcripts in the hippocampal formation of AD patients and age-matched controls is employed since this method allows a clear distinction of the classes of neurons and glia containing a particular message. Expand
Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3.
TLDR
The observation of two mutations in functionally different domains suggest that onset age and severity of AD may not be very helpful predictors of the location of putative S182 mutations. Expand
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
TLDR
A minimal cosegregating region containing the AD3 gene is defined, and at least 19 different transcripts encoded within this region corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Expand
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
TLDR
It is demonstrated that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene that causes an amino-acid substitution close to the carboxy terminus of the β-amyloid peptide. Expand
Mutations of the presenilin I gene in families with early-onset Alzheimer's disease.
TLDR
The results support the notion that PSNLI is the major gene involved in autosomal dominant EOAD, and underlines the great allelic heterogeneity and the large distribution of the mutations within thePSNLI coding region. Expand
Nonisotopic in situ hybridization of amyloid beta protein precursor in Alzheimer's disease: expression in neurofibrillary tangle bearing neurons and in the microenvironment surrounding senile plaques.
TLDR
The results suggest that no major change in distribution or type of APP mRNA accompanies neurofibrillary tangle or senile plaque development, which occurs primarily in CA1 and subiculum. Expand
Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
TLDR
It is demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. Expand
...
1
2
...