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In particular, the accumulation of intracellular A\u03b2, preceding extracellular plaque deposition, has been implicated in dysregulated excitability and early-stage neuronal stress. However, the molecular mechanisms linking intracellular A\u03b2 to altered neuronal excitability remain incompletely understood. This study aimed to identify a mediator of intracellular A\u03b2 toxicity contributing to neuronal dysfunction in A\u03b2 pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a genome-wide human protein chip assay, followed by in vitro binding assays, surface plasmon resonance, and in vivo colocalization analysis using postmortem Alzheimer\u2019s disease (AD) brain tissues in which A\u03b2 pathology is observed. We generated neuronal cell lines stably expressing mRFP-A\u03b2 to model intracellular A\u03b2 accumulation and investigate its pathogenic effects. In addition, we evaluated potassium channel activity and neurotoxicity in A\u03b2-treated neuronal cells and assessed neuronal excitability and cognitive functions in APP\n                      <jats:sup>NL\u2212G\u2212F<\/jats:sup>\n                      knock-in mice using electrophysiological recordings and behavioral tests.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Voltage-gated potassium channel \u03b22 (Kv\u03b22) was identified as a novel intracellular A\u03b2-binding protein. A\u03b2 directly bound to the N-terminus of Kv\u03b22, disrupting its interaction with EB1 and impairing Kv1-Kv\u03b22 localization to the axon initial segment. In neuronal cell lines expressing intracellular mRFP-A\u03b2, Kv\u03b22 colocalized with A\u03b2 in the cytosol, and Kv1 trafficking to the plasma membrane was markedly reduced. Consistent with this observation, colocalization of A\u03b2 and Kv\u03b22 was confirmed in the brains of AD patients. In addition, enforced expression of Kv\u03b22, but not A\u03b2-binding-defective Kv\u03b22 \u2206(2\u201318) mutant, rescued potassium channel dysfunction and suppressed neurotoxicity in A\u03b2-treated neuronal cells. Furthermore, lentiviral delivery of Kv\u03b22 into APP\n                      <jats:sup>NL\u2212G\u2212F<\/jats:sup>\n                      mice reduced neuronal hyperexcitability, rescued activity-related neuronal markers, and ameliorated memory deficits, whereas the Kv\u03b22 \u2206(2\u201318) mutant did not.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings suggest that the interaction between Kv\u03b22 and A\u03b2 mediates neuronal hyperexcitability and memory impairment in APP\n                      <jats:sup>NL\u2212G\u2212F<\/jats:sup>\n                      mice, elucidating a potential mechanism underlying Kv1 channel dysfunction in A\u03b2 pathology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-026-00936-2","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T09:23:28Z","timestamp":1773134608000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Altered trafficking of Kv1-Kv\u03b22 leads to neuronal hyperexcitability and memory deficits in amyloid-\u03b2 pathology"],"prefix":"10.1186","volume":"21","author":[{"given":"Young-Sin","family":"Cho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seo-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Hyeon","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaelin","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahyun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namhoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhah","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngwon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Gwak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Young","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi","family":"Saido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Keun","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"936_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.npep.2015.06.008","volume":"52","author":"SH Barage","year":"2015","unstructured":"Barage SH, Sonawane KD. 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