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

  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},
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… 
Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease
It is concluded that the published data provide strong evidence that APP has a trophic function and is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair.
The Function of the Amyloid Precursor Protein Family
This review will summarize the key activities associated with APP and its paralogues the amyloid precursor like proteins 1 and 2 (APLP1 and APLP2, respectively).
REVIEW: Pin1 in Alzheimer's disease
The role of Pin1 is discussed, which is found to be oxidatively modified and to have reduced activity in the hippocampus in mild cognitive impairment (MCI) and AD, and the discovery that this protein is one of the oxidized proteins common to both MCI and AD brain.
Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688
It is shown that ubiquilin-1 inhibits the maturation of APP by sequestering it in the early secretory pathway, primarily within the Golgi apparatus, with important consequences for the pathogenesis of late-onset AD.
Protein Phosphorylation is a Key Mechanism in Alzheimer's Disease.
This review focuses on some of the major protein kinases and protein phosphatases relevant to AD and highlights possible convergence points that may contribute to the different AD pathological hallmarks.
Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies
This review focuses on knockout and knockdown approaches that have provided insights into the physiological functions of APP and discusses their advantages and drawbacks.
Activation of neuronal defense mechanisms in response to pathogenic factors triggering induction of amyloidosis in Alzheimer's disease.
A new model for etiology of Alzheimer's disease (AD) is presented which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD and the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis is reviewed.
Neddylation dysfunction in Alzheimer's disease
Evidence suggesting that dysfunction of neddylation is involved in Alzheimer's disease is summarized and reviewed.
APP Gene
  • Biology
  • 2020
The APP gene provides instructions for making a protein called amyloid precursor protein, which is found in many tissues and organs, including the brain and spinal cord, and studies suggest that in the brain, it helps direct the movement of nerve cells (neurons) during early development.


Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide
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.
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 (*)
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
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
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.
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
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*
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