Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems

Alzheimer's disease (AD) is a progressive neurodegenerative disease and in its familial form is associated with mutations in the amyloid precursor protein (APP) and the presenilins (PSs). Much data regarding the interactions of APP, its proteolytic fragments and PS have been generated, expanding our understanding of the roles of these proteins in mechanisms underlying cognitive function and revealing many complex relationships with wide ranging cellular systems. In this review, we examine the multiple interactions of APP and its proteolytic fragments with other neuronal systems in terms of feedback loops and use these relationships to build a map. We highlight the complexity involved in the APP proteolytic system and discuss alternative perspectives on the roles of APP and its proteolytic fragments in dynamic processes associated with disease progression in AD. We highlight areas where data are missing and suggest potential confounding factors. We suggest that a systems biology approach enhances representations of the data and may be more useful in modelling both normal cognition and disease processes.

• Publication year

  2012

• Venue

  Alzheimer's Research & Therapy

• Publication date

  2012-04-13

• Fields of study

  Biology, Medicine, Computer Science

• Identifiers
  DOI 10.1186/alzrt108PMID 22498202PMCID 3583130
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• [PubMed].

  2020cited by this paper
• Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.

  2011influential reference
• APP processing in Alzheimer's disease

  2011influential reference
• Perspectives of a Systems Biology of the Synapse: How to Transform an Indefinite Data Space into a Model?

  2010cited by this paper
• Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains

  2010cited by this paper
• MatrixDB, the extracellular matrix interaction database

  2010cited by this paper
• Vulnerabilities in the Tau Network and the Role of Ultrasensitive Points in Tau Pathophysiology

  2010cited by this paper
• Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein

  2010cited by this paper
• A domain level interaction network of amyloid precursor protein and Aβ of Alzheimer's disease

  2010cited by this paper
• Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways

  2010influential reference
• Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain.

  2010cited by this paper
• Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

  2010cited by this paper
• Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer‐type pathology in the ageing brain

  2010cited by this paper
• sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress.

  2010cited by this paper
• Interaction of Reelin with Amyloid Precursor Protein Promotes Neurite Outgrowth

  2009cited by this paper
• In Vivo Turnover of Tau and APP Metabolites in the Brains of Wild-Type and Tg2576 Mice: Greater Stability of sAPP in the β-Amyloid Depositing Mice

  2009cited by this paper
• Alzheimer's Research & Therapy

  2009cited by this paper
• CD74 interacts with APP and suppresses the production of Aβ

  2009cited by this paper
• Molecular Dynamics Simulations to Investigate the Aggregation Behaviors of the Aß(17–42) Oligomers

  2009cited by this paper
• The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics

  2009cited by this paper
• Neuroprotective Secreted Amyloid Precursor Protein Acts by Disrupting Amyloid Precursor Protein Dimers*

  2009cited by this paper
• Interactions between the amyloid precursor protein C‐terminal domain and G proteins mediate calcium dysregulation and amyloid β toxicity in Alzheimer’s disease

  2009cited by this paper
• Age, neuropathology, and dementia.

  2009cited by this paper
• Reelin signaling antagonizes β-amyloid at the synapse

  2009cited by this paper
• NMDA receptor–dependent signaling pathways that underlie amyloid β‐protein disruption of LTP in the hippocampus

  2009cited by this paper
• A novel reciprocal and biphasic relationship between membrane cholesterol and β‐secretase activity in SH‐SY5Y cells and in human platelets

  2009cited by this paper
• β-Amyloid Impairs AMPA Receptor Trafficking and Function by Reducing Ca2+/Calmodulin-dependent Protein Kinase II Synaptic Distribution*

  2009cited by this paper
• Αβ Hinders Nuclear Targeting of AICD and Fe65 in Primary Neuronal Cultures

  2009cited by this paper
• Deciphering complex mechanisms in neurodegenerative diseases: the advent of systems biology.

  2009cited by this paper
• Alzheimer beta-amyloid blocks epileptiform activity in hippocampal neurons.

  2009cited by this paper
• Phosphorylation of a Tyrosine in the Amyloid-β Protein Precursor Intracellular Domain Inhibits Fe65 Binding and Signaling

  2009cited by this paper
• Changing perspectives regarding late-life dementia

  2009cited by this paper
• Interleukin‐1β enhances nucleotide‐induced and α‐secretase‐dependent amyloid precursor protein processing in rat primary cortical neurons via up‐regulation of the P2Y2 receptor

  2009cited by this paper
• The interactome of the amyloid β precursor protein family members is shaped by phosphorylation of their intracellular domains

  2009cited by this paper
• Variations in the transcriptome of Alzheimer's disease reveal molecular networks involved in cardiovascular diseases

  2008influential reference
• Complex of Amyloid β Peptides with 24-Hydroxycholesterol and Its Effect on Hemicholinium-3 Sensitive Carriers

  2008cited by this paper
• Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo.

  2008cited by this paper
• Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor

  2008cited by this paper
• Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1

  2008cited by this paper
• Inhibition of LTP in vivo by beta-amyloid peptide in different conformational states.

  2008cited by this paper
• Abeta(1-42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors.

  2008cited by this paper
• Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production.

  2008cited by this paper
• The aging brain.

  2008cited by this paper
• Alpha v integrins mediate beta-amyloid induced inhibition of long-term potentiation.

  2008cited by this paper
• Aβ1–42 modulation of Akt phosphorylation via α7 nAChR and NMDA receptors

  2008cited by this paper
• Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor?

  2008cited by this paper
• M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

  2008cited by this paper
• A Novel Sorting Nexin Modulates Endocytic Trafficking and α-Secretase Cleavage of the Amyloid Precursor Protein*

  2008cited by this paper
• Calcium dysregulation in Alzheimer's disease.

  2008cited by this paper
• Alpha4beta2 nicotinic acetylcholine receptors are required for the amyloid beta protein-induced suppression of long-term potentiation in rat hippocampal CA1 region in vivo.

  2008cited by this paper
• Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory.

  2008cited by this paper
• Interleukin‐1β up‐regulates TACE to enhance α‐cleavage of APP in neurons: resulting decrease in Aβ production

  2008cited by this paper
• Engineered Heparins: Novel β-Secretase Inhibitors as Potential Alzheimer’s Disease Therapeutics

  2008cited by this paper
• Interaction with amyloid beta peptide compromises the lipid binding function of apolipoprotein E.

  2008cited by this paper
• A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging

  2008influential reference
• αv integrins mediate beta-amyloid induced inhibition of long-term potentiation

  2008cited by this paper
• Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts.

  2007cited by this paper
• Internalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E*

  2007cited by this paper
• The Alzheimer's peptides Abeta40 and 42 adopt distinct conformations in water: a combined MD / NMR study.

  2007cited by this paper
• Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease.

  2007cited by this paper
• A ganglioside-induced toxic soluble Abeta assembly. Its enhanced formation from Abeta bearing the Arctic mutation.

  2007cited by this paper
• Neuropathological evaluation of mixed dementia.

  2007cited by this paper
• Effects of the monomeric, oligomeric, and fibrillar Aβ42 peptides on the proliferation and differentiation of adult neural stem cells from subventricular zone

  2007cited by this paper
• The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

  2007cited by this paper
• Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation.

  2007cited by this paper
• Abeta(1-40)-induced secretion of matrix metalloproteinase-9 results in sAPPalpha release by association with cell surface APP.

  2007cited by this paper
• A Ganglioside-induced Toxic Soluble Aβ Assembly

  2007cited by this paper
• The Metalloprotease Inhibitor TIMP-3 Regulates Amyloid Precursor Protein and Apolipoprotein E Receptor Proteolysis

  2007cited by this paper
• Calcium and neurodegeneration

  2007cited by this paper
• Electrophysiological and cerebrovascular effects of the alpha-secretase-derived form of amyloid precursor protein in young and middle-aged rats.

  2007cited by this paper
• Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation*

  2007cited by this paper
• Amyloid Precursor Protein and BACE Function as Oligomers

  2006cited by this paper
• The involvement of lipid rafts in Alzheimer's disease (Review)

  2006cited by this paper
• Furin is an endogenous regulator of α-secretase associated APP processing

  2006cited by this paper
• Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases.

  2006cited by this paper
• Abeta42 is more rigid than Abeta40 at the C terminus: implications for Abeta aggregation and toxicity.

  2006cited by this paper
• Nuclear Factor-κB Activated by Capacitative Ca2+ Entry Enhances Muscarinic Receptor-mediated Soluble Amyloid Precursor Protein (sAPPα) Release in SH-SY5Y Cells*

  2006cited by this paper
• Heparin activates beta-secretase (BACE1) of Alzheimer's disease and increases autocatalysis of the enzyme.

  2006cited by this paper
• Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer‐like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein

  2006cited by this paper
• Nuclear factor-kappaB activated by capacitative Ca2+ entry enhances muscarinic receptor-mediated soluble amyloid precursor protein (sAPPalpha) release in SH-SY5Y cells.

  2006cited by this paper
• Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein.

  2006cited by this paper
• Furin is an endogenous regulator of alpha-secretase associated APP processing.

  2006cited by this paper
• BACE2, as a novel APP θ‐secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome

  2006cited by this paper
• Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease.

  2006influential reference
• Influence of heparin and dendrimers on the aggregation of two amyloid peptides related to Alzheimer's and prion diseases.

  2006cited by this paper
• DAB1 and Reelin Effects on Amyloid Precursor Protein and ApoE Receptor 2 Trafficking and Processing*

  2006cited by this paper
• M1 receptors play a central role in modulating AD-like pathology in transgenic mice.

  2006cited by this paper
• The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

  2006cited by this paper
• Aβ42 is More Rigid than Aβ40 at the C Terminus: Implications for Aβ Aggregation and Toxicity

  2006cited by this paper
• P2Y2 Nucleotide Receptors Enhance α-Secretase-dependent Amyloid Precursor Protein Processing*

  2005cited by this paper
• Regulation of NMDA receptor trafficking by amyloid-beta.

  2005cited by this paper
• Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques.

  2005cited by this paper
• Expression of human FE65 in amyloid precursor protein transgenic mice is associated with a reduction in β‐amyloid load

  2005cited by this paper
• P2Y2 nucleotide receptors enhance alpha-secretase-dependent amyloid precursor protein processing.

  2005cited by this paper
• Regulation of NMDA receptor trafficking by amyloid-β

  2005cited by this paper
• Physiological levels of amyloid peptides stimulate the angiogenic response through FGF‐2

  2004cited by this paper
• Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice.

  2004cited by this paper
• Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation.

  2004cited by this paper
• Neuropathological stageing of Alzheimer-related changes

  2004cited by this paper
• Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications.

  2004cited by this paper

• Key questions for the future of amyloid research in dementia: a framework for integrating complex datasets

  2025cites this paper
• Unraveling the Function of PPARα in Neurodegenerative Disorders: A Potential Pathway to Novel Therapies

  2025cites this paper
• Amyloid precursor protein induces reactive astrogliosis

  2024cites this paper
• Amyloid precursor protein induces reactive astrogliosis

  2023cites this paper
• Amyloid in the ageing brain: New frameworks and perspectives

  2021cites this paper
• The amyloid precursor protein is a conserved Wnt receptor

  2021cites this paper
• Reappraisal of FDA approved drugs against Alzheimer’s disease based on differential gene expression and protein interaction network analysis: an in silico approach

  2020cites this paper
• His6, His13, and His14 residues in Aβ 1–40 peptide significantly and specifically affect oligomeric equilibria

  2019cites this paper
• Title: Biochemical linkage of type 2 diabetes mellitus and Alzheimer’s disease

  2019cites this paper
• Inner Workings: Family of protein fragments promises fresh view of Alzheimer's disease

  2019cites this paper
• Aβ and the dementia syndrome: Simple versus complex perspectives

  2018cites this paper
• Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer’s Disease (PS1V97L) Transgenic Mice

  2018cites this paper
• Understanding the roles of mutations in the amyloid precursor protein in Alzheimer disease

  2018cites this paper
• Dementia Research: Populations, Progress, Problems, and Predictions

  2018cites this paper
• Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer’s Disease Neuronal Cell Culture Models

  2018cites this paper
• Positive Feedback Loops in Alzheimer’s Disease: The Alzheimer’s Feedback Hypothesis

  2018cites this paper
• Side-chain moieties from the N-terminal region of Aβ are Involved in an oligomer-stabilizing network of interactions

  2018cites this paper
• Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research?

  2017cites this paper
• NeuronRead, an open source semi‐automated tool for morphometric analysis of phase contrast and fluorescence neuronal images

  2017cites this paper
• Multi-Targeting Derivatives For Alzheimer’s Disease: Utilization of Quinazoline Ring Scaffolds

  2016influential citation
• The APP Proteolytic System and Its Interactions with Dynamic Networks in Alzheimer's Disease.

  2016cites this paper
• Solanezumab and the amyloid hypothesis for Alzheimer’s disease

  2016cites this paper
• Immune responses to amyloid beta and post-translationally modified variants

  2016influential citation
• Alzheimer's as a Systems-Level Disease Involving the Interplay of Multiple Cellular Networks.

  2016cites this paper
• Activation of 5-HT2C Receptor Promotes the Expression of Neprilysin in U251 Human Glioma Cells

  2015cites this paper
• Changes in the expression of BNIP-3 and other neuronal factors during the cultivation period of primary cultured rat cerebral cortical neurons and an assessment of each factor's functions

  2014cites this paper
• Adapting to Dementia in Society: A Challenge for Our Lifetimes and a Charge for Public Health

  2014cites this paper
• Integrating the molecular and the population approaches to dementia research to help guide the future development of appropriate therapeutics.

  2014cites this paper
• The Senescence Hypothesis of Disease Progression in Alzheimer Disease: an Integrated Matrix of Disease Pathways for FAD and SAD

  2013influential citation
• The Development of an in vivo γ-Secretase Assay using Zebrafish Embryos

  2013cites this paper
• Localization of secretases involved in the processing of β- Amyloid precursor protein related to alzheimer’s disease

  2013cites this paper
• BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease

  2012cites this paper