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

  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 Lieberburg and Dennis J. Selkoe},
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… 
The amyloid beta protein precursor mutations linked to familial Alzheimer's disease alter processing in a way that fosters amyloid deposition.
  • S. Younkin
  • Biology
    The Tohoku journal of experimental medicine
  • 1994
The data show that all of the FAD-linked beta APP mutations alter beta APP processing in a way that increases the likelihood of amyloid formation.
Phosphorylation of amyloid beta (Aβ) peptides – A trigger for formation of toxic aggregates in Alzheimer's disease
These findings demonstrate a novel molecular mechanism that triggers aggregation and toxicity of Aβ, and the identification of extracellular protein kinase A should also stimulate pharmacological approaches to decrease Aβ phosphorylation in the therapy and/or prevention of AD.
Amyloid Precursor Protein, Presenilins, and α-Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Treatments that block the accumulation of Aβ and α-synuclein might benefit a broad spectrum of neurodegenerative disorders, because some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways.
Alzheimer’s Disease and Hemorrhagic Stroke: Their Relationship to βA4 Amyloid Deposition
Distinct mutations have been reported in approximately 5% of early-onset Alzheimer disease (AD) families in the gene coding for the amyloid precursor protein (APP) located at chromosome 21q21.2.
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  • Biology
    Cellular and Molecular Life Sciences CMLS
  • 1998
In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing of APP, resulting in an increase in the production of Aβ42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain.
Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease
The reported cellular phenotypes of APP and PSEN mutations, the current understanding of their molecular mechanisms, the need to generate faithful models of PSEN mutation, and the potential bias ofAPP andPSEN mutations on therapeutic strategies that target Aβ are discussed.
What do we learn from a few familial Alzheimer's disease cases?
Interestingly, mutations in the Presenilin genes which are responsible for more then 40% of all familial AD cases also cause enhanced production of the elongated form of A beta, which strongly supports the amyloid cascade hypothesis.
The molecular significance of amyloid β-peptide for Alzheimer's disease
  • C. Haass
  • Biology
    European Archives of Psychiatry and Clinical Neuroscience
  • 2005
Alzheimer's disease is the most common form of dementia. Although the majority of the cases occur sporadically, in some rare cases Alzheimer's disease is genetically inherited. Pathologically,


A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid
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.
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
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
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
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.
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.
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.
Amyloid β-peptide is produced by cultured cells during normal metabolism
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.
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It is demonstrated that Aβ is produced and released both in vivo and in vitro, and new opportunities for developing diagnostic tests for Alzheimer's disease and therapeutic strategies aimed at reducing the cerebral deposition of Aβ are offered.