ArticleMolecular brain2015
Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes.
Article in Molecular brain, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- Article
- The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.bioRxiv : the preprint server for biology · 2026Article
- EFA6A, a Guanine Nucleotide Exchange Factor for Arf6, Regulates Developmental Stage-Dependent Spine Morphogenesis, Synaptic Plasticity, and Long-Term Memory in the Hippocampus.Molecular neurobiology · 2025Article
- Microglial activation states and their implications for Alzheimer's Disease.The journal of prevention of Alzheimer's disease · 2025Review
- Small GTPases control macropinocytosis of amyloid precursor protein and cleavage to amyloid-β.Heliyon · 2024Article
- α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.Cell reports · 2023Article
- Review
- Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction.International journal of molecular sciences · 2023Article
- Review
- Physiological and Pathological Roles of the Cytohesin Family in Neurons.International journal of molecular sciences · 2022Review
- Revealing macropinocytosis using nanoparticles.Molecular aspects of medicine · 2022Review
- Amyloid Beta Is InternalizedFrontiers in molecular neuroscience · 2022Article
- The acute phase protein lactoferrin is a key feature of Alzheimer's disease and predictor of Aβ burden through induction of APP amyloidogenic processing.Molecular psychiatry · 2021Article
- Review
- Review
- Par3 regulates polarized convergence between APP and BACE1 in hippocampal neurons.Neurobiology of aging · 2019Article
- Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration-approved drugs.British journal of pharmacology · 2018Article
- Genetic study of multimodal imaging Alzheimer's disease progression score implicates novel loci.Brain : a journal of neurology · 2018Article
- Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1.Neurobiology of aging · 2017Article
- APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins.Frontiers in molecular neuroscience · 2017Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production.
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