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Neuronal Activity-dependent APP Processing

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Neuronal-Activity-dependent-APP-Processing

Pathway Description:

The amyloid precursor protein (APP) 695 isoform is a type I transmembrane protein that is neuronally expressed and contains amyloidogenic Aβ monomer fragments that are genetically and biochemically implicated in Alzheimer’s disease (AD). Such Aβ monomers result from one of two possible post-translational proteolytic cleavage routes, the determination of which is dependent on many factors including neuronal activity as well as the localization of APP and respective proteolytic secretases. The critical choice point occurs with initial cleavage of APP; proteolysis by α-secretases, such as ADAM10, that reside in the cell membrane generate extracellular soluble APPα (sAPPα) and prevent Aβ formation, as α-secretase cleavage occurs within the Aβ domain. However, alternative cleavage by β-secretases such as BACE1, often occurring in endosomes, preserves the Aβ domain and subsequent cleavage by γ-secretase yields amyloidogenic Aβ monomers. Mutations in γ-secretase complex proteins presenilin 1 and 2 are causative of early-onset AD, presumably due to enhanced generation of Aβ monomers. In the normal state, the α-secretase cleavage pathway is favored, producing the sAPPα and AICD fragments, which play critical roles in healthy neuronal development, maintenance, and function. Yet a predominance towards β-secretase cleavage both attenuates the amount of beneficial sAPPα and increases the production of prion-like Aβ monomers, which can accumulate intracellularly or be trafficked to the cell surface for extracellular release. These monomers self-aggregate into oligomer-built fibrils that accumulate to form extracellular Aβ plaques. These plaques, which are hallmarks of both familial and spontaneous AD, trigger neuroinflammatory pathways and are associated with neurodegeneration and cognitive decline.

Selected Reviews:

created December 2021
Acetylase
Acetylase
Metabolic Enzyme
Metabolic Enzyme
Adaptor
Adaptor
Methyltransferase or G-protein
Methyltransferase or G-protein
Adaptor
Apoptosis/Autophagy Regulator
Phosphatase
Phosphatase
Cell Cycle Regulator
Cell Cycle Regulator
Protein Complex
Protein Complex
Deacetylase or Cytoskeletal Protein
Deacetylase or Cytoskeletal Protein
Ubiquitin/SUMO Ligase or Deubiquitinase
Ubiquitin/SUMO Ligase or Deubiquitinase
Growth Factor/Cytokine/Development Protein
Growth Factor/Cytokine/Development Protein
Transcription Factor or Translation Factor
Transcription Factor or Translation Factor
GTPase/GAP/GEF
GTPase/GAP/GEF
Receptor
Receptor
Kinase
Kinase
Other
Other
 
Direct Process
Direct Process
Tentative Process
Tentative Process
Translocation Process
Translocation Process
Stimulatory Modification
Stimulatory Modification
Inhibitory Modification
Inhibitory Modification
Transcriptional Modification
Transcriptional Modification