{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:43:02Z","timestamp":1792651382177,"version":"4.5.0"},"reference-count":77,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,10]],"date-time":"2022-04-10T00:00:00Z","timestamp":1649548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020396","name":"Alzheimers New Zealand","doi-asserted-by":"publisher","award":["3718869"],"award-info":[{"award-number":["3718869"]}],"id":[{"id":"10.13039\/501100020396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003189","name":"Freemasons New Zealand","doi-asserted-by":"publisher","award":["3719321"],"award-info":[{"award-number":["3719321"]}],"id":[{"id":"10.13039\/501100003189","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020395","name":"Alzheimers New Zealand Charitable Trust","doi-asserted-by":"publisher","award":["3720863"],"award-info":[{"award-number":["3720863"]}],"id":[{"id":"10.13039\/501100020395","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["3627373"],"award-info":[{"award-number":["3627373"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001543","name":"Neurological Foundation of New Zealand","doi-asserted-by":"publisher","award":["3723991"],"award-info":[{"award-number":["3723991"]}],"id":[{"id":"10.13039\/501100001543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder with an increasing need for developing disease-modifying treatments as current therapies only provide marginal symptomatic relief. Recent evidence suggests the \u03b3-aminobutyric acid (GABA) neurotransmitter system undergoes remodeling in AD, disrupting the excitatory\/inhibitory (E\/I) balance in the brain. Altered expression levels of K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), which are cation\u2013chloride cotransporters (CCCs), have been implicated in disrupting GABAergic activity by regulating GABAA receptor signaling polarity in several neurological disorders, but these have not yet been explored in AD. NKCC1 and KCC2 regulate intracellular chloride [Cl\u2212]i by accumulating and extruding Cl\u2212, respectively. Increased NKCC1 expression in mature neurons has been reported in these disease conditions, and bumetanide, an NKCC1 inhibitor, is suggested to show potential therapeutic benefits. This study used primary mouse hippocampal neurons to explore if KCC2 and NKCC1 expression levels are altered following beta-amyloid (A\u03b21-42) treatment and the potential neuroprotective effects of bumetanide. KCC2 and NKCC1 expression levels were also examined in 18-months-old male C57BL\/6 mice following bilateral hippocampal A\u03b21-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM A\u03b21-42, but NKCC1 expression increased 30-days post-A\u03b21-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM A\u03b21-42 alone or with various concentrations of bumetanide (1 \u00b5M, 10 \u00b5M, 100 \u00b5M, 1 mM) to investigate the effect of the drug on cell viability. A\u03b21-42 produced 53.1 \u00b1 1.4% cell death after 5 days, and the addition of bumetanide did not reduce this. However, the drug at all concentrations significantly reduced cell viability, suggesting bumetanide is highly neurotoxic. In summary, these results suggest that chronic exposure to A\u03b21-42 alters the balance of KCC2 and NKCC1 expression in a region-and layer-specific manner in mouse hippocampal tissue; therefore, this process most likely contributes to altered hippocampal E\/I balance in this model. Furthermore, bumetanide induces hippocampal neurotoxicity, thus questioning its suitability for AD therapy. Further investigations are required to examine the effects of A\u03b21-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD.<\/jats:p>","DOI":"10.3390\/molecules27082440","type":"journal-article","created":{"date-parts":[[2022,4,10]],"date-time":"2022-04-10T06:02:54Z","timestamp":1649570574000},"page":"2440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Beta-Amyloid (A\u03b21-42) Increases the Expression of NKCC1 in the Mouse Hippocampus"],"prefix":"10.3390","volume":"27","author":[{"given":"Patricia","family":"Lam","sequence":"first","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitra","family":"Vinnakota","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Calvo-Flores","family":"Guzma\u0301n","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Newland","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Peppercorn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren P.","family":"Tate","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry J.","family":"Waldvogel","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L. M.","family":"Faull","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-4956","authenticated-orcid":false,"given":"Andrea","family":"Kwakowsky","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"},{"name":"Pharmacology and Therapeutics, Galway Neuroscience Centre, School of Medicine, National University of Ireland Galway, H91 W5P7 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological staging of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Govindpani, K., Guzm\u00e1n, B.C.-F., Vinnakota, C., Waldvogel, H.J., Faull, R.L., and Kwakowsky, A. 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