Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production

@article{Citron1992MutationOT,
  title={Mutation of the $\beta$-amyloid precursor protein in familial Alzheimer's disease increases $\beta$-protein production},
  author={Martin O. Citron and Tilman Oltersdorf and Christian Haass and Lisa McConlogue and Albert Y Hung and Peter Seubert and Carmen Vigo‐Pelfrey and Ivan M. Lieberburg and Dennis J. Selkoe},
  journal={Nature},
  year={1992},
  volume={360},
  pages={672-674}
}
PROGRESSIVE cerebral deposition of the 39–43-amino-acid amy-loid β-protein (Aβ) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the β-amyloid precursor protein (β3-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD)1–5. These mutations are… 

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...

References

SHOWING 1-10 OF 17 REFERENCES

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid

TLDR
A double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co–segregates with the disease in two large (probably related) early–onset Alzheimer's disease families from Sweden is identified.

A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.

TLDR
Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein, which may be the inherited factor causing both amyloids fibril formation and dementia.

Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β–amyloid precursor protein gene

TLDR
A novel base mutation in the same exon of the APP gene which co–segregates in one family with presenile dementia and cerebral haemorrhage due to cerebral amyloid angiopathy is reported, suggesting that the clinically distinct entities can be caused by the same mutation.

The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor

TLDR
An apparently full-length complementary DNA clone coding for the A4 polypeptide is isolated and sequenced and suggests that the cerebral amyloid deposited in Alzheimer's disease and aged Down's syndrome is caused by aberrant catabolism of a cell-surface receptor.

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.

Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues.

TLDR
It is concluded that the highly conserved beta APP molecule occurs in mammalian tissues as a heterogeneous group of membrane-associated proteins of approximately 120 kDa.

Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing.

TLDR
An early event in amyloid formation may involve altered APP processing that results in the release and subsequent deposition of intact beta/A4, which is the principal component of senile plaques in Alzheimer's disease.

Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.

TLDR
Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidsosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the ameloid protein.

Amyloid β-peptide is produced by cultured cells during normal metabolism

TLDR
The unexpected identification of the 4K (Mr 4,000) Aβ and a truncated form of Aβ in media from cultures of primary cells and untransfected and β-APP-transfected cell lines grown under normal conditions provide the basis for using simple cell culture systems to identify drugs that block the formation or release of A β, the primary protein constituent of the senile plaques of Alzheimer's disease.

Production of the Alzheimer amyloid beta protein by normal proteolytic processing.

TLDR
Human mononuclear leukemic cells expressing a beta AP-bearing, carboxyl-terminal beta APP derivative released significant amounts of a soluble 4-kilodalton beta AP derivative essentially identical to the beta AP deposited in Alzheimer's disease.