ArticleThe Journal of biological chemistry2015
The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer disease.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 69 citations in OpenAlex.
- Histone deacetylase-mediated regulation of endolysosomal pH.The Journal of biological chemistry · 2018Pooled it
- High-resolution structures of human NHE6 and NHE9 elucidate endosomal ion and lipid interactions.Nature communications · 2026Article
- Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH.Nature communications · 2026Article
- Integrative structural analysis of human endosomal NHE6 reveals a lipid-associated gate and disordered C-terminus.Nature communications · 2026Article
- The Recycling Endosomal (NaActa physiologica (Oxford, England) · 2026Article
- TOM1 family proteins: from cargo sorting to immune dysregulation and cancer.Cell communication and signaling : CCS · 2026Review
- Review
- Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.Journal of nanobiotechnology · 2026Article
- Levetiracetam prevents Aβ production through SV2a-dependent modulation of APP processing in Alzheimer's disease models.Science translational medicine · 2026Article
- The Christianson syndrome protein, sodium hydrogen exchanger isoform 6, is required for fat accumulation.The Journal of physiology · 2025Article
- Alterations in the NaCerebellum (London, England) · 2025Article
- Article
- Linking endo-lysosomal pH, sterol, and trafficking to neurodegenerative disease.FEMS yeast research · 2025Review
- Endosomal pH is an evolutionarily conserved driver of phenotypic plasticity in colorectal cancer.NPJ systems biology and applications · 2024Article
- GGA1 interacts with the endosomal Na+/H+ exchanger NHE6 governing localization to the endosome compartment.The Journal of biological chemistry · 2024Article
- A DNA nanodevice for mapping sodium at single-organelle resolution.Nature biotechnology · 2024Article
- Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice.International journal of molecular sciences · 2024Article
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
- Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat.Human molecular genetics · 2023Article
- Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases.Reviews of physiology, biochemistry and pharmacology · 2023Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na(+)/H(+) exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 or treatment with the Na(+)/H(+) ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. We show that NHE6 transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na(+)/H(+) exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.