Cytoplasmic domain of the β‐amyloid protein precursor of Alzheimer's disease: Function, regulation of proteolysis, and implications for drug development

@article{Kerr2005CytoplasmicDO,
  title={Cytoplasmic domain of the $\beta$‐amyloid protein precursor of Alzheimer's disease: Function, regulation of proteolysis, and implications for drug development},
  author={Megan L Kerr and David Henry Small},
  journal={Journal of Neuroscience Research},
  year={2005},
  volume={80}
}
The β‐amyloid protein precursor (APP) has been extensively studied for its role in amyloid production and the pathogenesis of Alzheimer's disease (AD). However, little is known about the normal function of APP and its biological interactions. In this Mini‐Review, the role of the cytoplasmic domain of APP in APP trafficking and proteolysis is described. These studies suggest that proteins that bind to the cytoplasmic domain may be important targets for drug development in AD. © 2005 Wiley‐Liss… 
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  • Biology
    Definitions
  • 2020
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References

SHOWING 1-10 OF 135 REFERENCES
Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide
TLDR
Evidence is reported that a substantial portion of the APP secreted by human mixed brain cell cultures, as well as that present in cerebrospinal fluid, is of a novel form cleaved precisely at the amino terminus of Aβ, suggesting that a secretory pathway is involved in Aβ genesis.
Cleavage of amyloid beta peptide during constitutive processing of its precursor.
TLDR
Direct protein structural analyses showed that constitutive processing in human embryonic kidney 293 cells cleaves APP in the interior of the A Beta P, thus preventing A beta P deposition.
APP-BP1, a Novel Protein That Binds to the Carboxyl-terminal Region of the Amyloid Precursor Protein (*)
TLDR
The cloning of a cDNA encoding a ubiquitously expressed 59-kDa APP-binding protein, called APP-BP1, is 61% similar to a protein encoded by the Arabidopsis AXR1 gene, required for normal response to the hormone auxin, and is a relative of the ubiquitin activating enzyme E1.
Alzheimer's Disease Therapeutics: New Approaches to an Ageing Problem
TLDR
This review examines the potential of immunization strategies, cholesterol‐lowering drugs, protease inhibitors and nicotinic drugs for the treatment of AD.
Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity
TLDR
Asp2 is a new protein target for drugs that are designed to block the production of amyloid β-peptide peptide and the consequent formation ofAmyloid plaque in Alzheimer's disease.
Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease.
TLDR
A peptide derived from the amyloid precursor may be neurotoxic, and conditioned medium from these cells was toxic to neurons in primary hippocampal cultures, and the toxic agent could be removed by immunoabsorption with an antibody directed against theAmyloid polypeptide.
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.
Phosphorylation-dependent Regulation of the Interaction of Amyloid Precursor Protein with Fe65 Affects the Production of β-Amyloid*
TLDR
The present results suggest that the phosphorylation of O-glycosylated mature APP at Thr-668 causes a conformational change in its cytoplasmic domain that prevents binding of Fe65 in neurons and may lead to an alteration in the production of Aβ.
Regulation of APP cleavage by α‐, β‐ and γ‐secretases
...
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