Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides

  title={Distinct sites of intracellular production for Alzheimer's disease A$\beta$40/42 amyloid peptides},
  author={Tobias Hartmann and Sophie Bieger and Babara Br{\"u}hl and Pentti J. Tienari and Nobuo Ida and David Allsop and Gareth W. Roberts and Colin L. Masters and Carlos G Dotti and Klaus Unsicker and Konrad T. Beyreuther},
  journal={Nature Medicine},
The Alzheimer amyloid precursor protein (APP) is cleaved by several proteases, the most studied, but still unidentified ones, are those involved in the release of a fragment of APP, the amyloidogenic β-protein Aβ. Proteolysis by γ-secretase is the last processing step resulting in release of Aβ. Cleavage occurs after residue 40 of Aβ [Aβ(1–40)], occasionally after residue 42 [Aβ(1–42)]. Even slightly increased amounts of this Aβ(1–42) might be sufficient to cause Alzheimer's disease (AD… 
The involvement of lipid rafts in Alzheimer's disease (Review)
Evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane.
Proteolytic processing of Alzheimer's disease associated proteins.
It is demonstrated that PS proteins are involved in NOTCH signaling FAD causing mutations interfere with the biological function of PS proteins in NotCH signaling.
Closing in on the amyloid cascade
What is know about BACE and the presenilins, focusing on their capacity as secretases, as well as the options for therapeutic advancement the careful characterization of these proteins will provide are discussed.
Review Alzheimer ß-amyloid peptides: normal and abnormal localization
Current knowledge of the localization of both intracellular and extracellular As is outlined, which shows that As is generated in the ER, Golgi, and endosomal/lysosomal system and causes toxicity to surrounding neurons as extacellular SP.
APP processing in Alzheimer's disease
Current knowledge of APP processing regulation as well as the patho/physiological functions of APP and its metabolites are reviewed.
Post-translational processing of proteins implicated in the pathogenesis of Alzheimer's disease
This work emphasised the need to use antibodies that distinguish between APP and APLP2 (which does not contain the beta-amyloid sequence) in studies of APP processing and amyloidogenesis, since only APP was concentrated in compartments beyond the Golgi apparatus.
The amyloid precursor protein of Alzheimer’s disease and the Aβ peptide
The central role of amyloid in the pathogenesis of Alzheimer’s disease is focused on, and the site of γ‐secretase cleavage is critical to the development of ameloid deposits.
Cellular mechanisms of beta-amyloid production and secretion.
  • S. Sinha, I. Lieberburg
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
Peptide aldehyde inhibitors that block Abeta production by inhibiting gamma-secretase cleavage of beta-CTF have been discovered, indicating that PS-1 expression is important for gamma- secretase cleavages.
The major premise of this thesis was to follow the turnover of proteins in the cell: from synthesis and quality control in the endoplasmic reticulum, trafficking along the secretory pathway to a protein’s site of action and finally protein degradation by the proteasome, and demonstrated that all these pathways are significant for neurodegenerative disorders, such as Alzheimer's disease.


Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42*
It is demonstrated that the γ-secretase cleavage of Aβ after amino acid 42 can occur within the ER and later within the secretory pathway within the Golgi.
Normal Cellular Processing of the β‐Amyloid Precursor Protein Results in the Secretion of the Amyloid β Peptide and Related Molecules a
The finding that Aβ is produced continuously by normal processing in tissue culture cells is described and it is concluded that lysosomes may not play a predominant role in the formation of 3 and 4 kDa peptides.
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.
Intracellular and secreted Alzheimer beta-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons.
It is shown that hippocampal neurons are able to utilize an alternate pathway to produce intracellular beta A4, and a common feature of two types of APP mutations implicated in early-onset AD is their increased production of C-terminally elongatedbeta A4 (beta 42), both intra- and extracellularly.
Intracellular production of beta A4 amyloid of Alzheimer's disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein.
The results therefore demonstrate a double dissociation between the secretion of sAPP and beta A4 in the SH-SY5Y cell line, and supports previous studies which show that metalloproteases are involved in the biogenesis of Beta A4.
Production of the Alzheimer amyloid beta protein by normal proteolytic processing.
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.