Beta-Amyloid (Aβ1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus

Show simple item record Lam, Patricia Vinnakota, Chitra Guzmán, Beatriz Calvo-Flores Newland, Julia Peppercorn, Katie Tate, Warren P Waldvogel, Henry J Faull, Richard LM Kwakowsky, Andrea 2022-05-16T03:23:36Z 2022-05-16T03:23:36Z 2022-04-10
dc.identifier.citation (2022). Molecules, 27(8), 2440-.
dc.identifier.issn 1420-3049
dc.description.abstract <jats:p>Alzheimer’s 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 γ-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–chloride 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−]i by accumulating and extruding Cl−, 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 (Aβ1-42) 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 Aβ1-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM Aβ1-42, but NKCC1 expression increased 30-days post-Aβ1-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM Aβ1-42 alone or with various concentrations of bumetanide (1 µM, 10 µM, 100 µM, 1 mM) to investigate the effect of the drug on cell viability. Aβ1-42 produced 53.1 ± 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 Aβ1-42 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 Aβ1-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD.</jats:p>
dc.language en
dc.publisher MDPI AG
dc.relation.ispartofseries Molecules
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.
dc.subject Dementia
dc.subject Neurodegenerative
dc.subject Acquired Cognitive Impairment
dc.subject Aging
dc.subject Neurosciences
dc.subject Alzheimer's Disease
dc.subject Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
dc.subject Brain Disorders
dc.subject 2.1 Biological and endogenous factors
dc.subject 5.1 Pharmaceuticals
dc.subject Neurological
dc.subject 0304 Medicinal and Biomolecular Chemistry
dc.subject 0305 Organic Chemistry
dc.subject 0307 Theoretical and Computational Chemistry
dc.title Beta-Amyloid (Aβ1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus
dc.type Journal Article
dc.identifier.doi 10.3390/molecules27082440
pubs.issue 8
pubs.begin-page 2440
pubs.volume 27 2022-04-20T10:13:24Z
dc.rights.holder Copyright: The author en
pubs.publication-status Published online
dc.rights.accessrights en
pubs.elements-id 896434 Medical and Health Sciences Medical Sciences Anatomy and Medical Imaging
dc.identifier.eissn 1420-3049
pubs.record-created-at-source-date 2022-04-20 2022-04-10

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