ArticleMolecular brain2014
The Amyloid Precursor Protein is rapidly transported from the Golgi apparatus to the lysosome and where it is processed into beta-amyloid.
Article in Molecular brain, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 76 citations in OpenAlex.
- A Question of Origins: Non-neuronal Sources of Amyloid-β.Neuroscience bulletin · 2026Review
- Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis.Molecular neurodegeneration advances · 2026Article
- RABGAP1 is a sensor that facilitates the sorting and processing of amyloid precursor protein.The EMBO journal · 2025Article
- Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations.The Biochemical journal · 2024Review
- Protein Kinase C (PKC) in Neurological Health: Implications for Alzheimer's Disease and Chronic Alcohol Consumption.Brain sciences · 2024Review
- Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment.Cell reports · 2023Article
- AP2S1 regulates APP degradation through late endosome-lysosome fusion in cells and APP/PS1 mice.Traffic (Copenhagen, Denmark) · 2023Article
- Spatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics.Nature communications · 2022Article
- Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer's Disease.Biomedicines · 2022Review
- Enhanced cleavage of APP by co-expressed Bace1 alters the distribution of APP and its fragments in neuronal and non-neuronal cells.Molecular neurobiology · 2022Article
- Poloxamer-188 Exacerbates Brain Amyloidosis, Presynaptic Dystrophies, and Pathogenic Microglial Activation in 5XFAD Mice.Current Alzheimer research · 2022Article
- Brain Exosomes: Friend or Foe in Alzheimer's Disease?Molecular neurobiology · 2021Review
- Endosomal-lysosomal dysfunctions in Alzheimer's disease: Pathogenesis and therapeutic interventions.Metabolic brain disease · 2021Review
- A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration.Frontiers in pharmacology · 2021Article
- Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer's Disease.Journal of personalized medicine · 2020Article
- The Other Side of Alzheimer's Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers.Journal of personalized medicine · 2020Review
- Molecular Mechanisms of ER Stress and UPR in the Pathogenesis of Alzheimer's Disease.Molecular neurobiology · 2020Review
- Heart and Brain: Complex Relationships for Left Ventricular Dysfunction.Current cardiology reports · 2020Review
- Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer's Pathogenesis.Molecules (Basel, Switzerland) · 2020Review
- APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells.International journal of molecular sciences · 2020Article
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3 authors at 1 institution in 1 country.
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Abstract
backgroundAlzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid peptide (Aβ). Aβ is produced by sequential cleavage of the Amyloid Precursor Protein (APP) by β- and γ-secretases. Many studies have demonstrated that the internalization of APP from the cell surface can regulate Aβ production, although the exact organelle in which Aβ is produced remains contentious. A number of recent studies suggest that intracellular trafficking also plays a role in regulating Aβ production, but these pathways are relatively under-studied. The goal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular APP processing.
resultsWe have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein (paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the Golgi to downstream compartments identified with compartment markers tagged with red fluorescent protein (mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because γ-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of fluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that APP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the highly selective γ-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is being cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal APP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3 (AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we are able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces Aβ production by more than a third.
conclusionThese data suggests that AP-3 mediates rapid delivery of APP to lysosomes, and that the lysosome is a likely site of Aβ production.
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