Disruption of sphingomyelin synthase 2 gene alleviates cognitive impairment in a mouse model of Alzheimer's disease.

Autor: Uchiumi O; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan., Zou J; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; First Affiliated Hospital, China Medical University, Shenyang 110001, China., Yamaki S; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan., Hori Y; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan., Ono M; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan., Yamamoto R; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan., Kato N; Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan. Electronic address: kato@kanazawa-med.ac.jp.
Jazyk: angličtina
Zdroj: Brain research [Brain Res] 2024 Jul 15; Vol. 1835, pp. 148934. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1016/j.brainres.2024.148934
Abstrakt: The membrane raft accommodates the key enzymes synthesizing amyloid β (Aβ). One of the two characteristic components of the membrane raft, cholesterol, is well known to promote the key enzymes that produce amyloid-β (Aβ) and exacerbate Alzheimer's disease (AD) pathogenesis. Given that the raft is a physicochemical platform for the sound functioning of embedded bioactive proteins, the other major lipid component sphingomyelin may also be involved in AD. Here we knocked out the sphingomyelin synthase 2 gene (SMS2) in 3xTg AD model mice by hybridization, yielding SMS2KO mice (4S mice). The novel object recognition test in 9/10-month-old 4S mice showed that cognitive impairment in 3xTg mice was alleviated by SMS2KO, though performance in the Morris water maze (MWM) was not improved. The tail suspension test detected a depressive trait in 4S mice, which may have hindered the manifestation of performance in the wet, stressful environment of MWM. In the hippocampal CA1, hyperexcitability in 3xTg was also found alleviated by SMS2KO. In the hippocampal dentate gyrus of 4S mice, the number of neurons positive with intracellular Aβ or its precursor proteins, the hallmark of young 3xTg mice, is reduced to one-third, suggesting an SMS2KO-led suppression of syntheses of those peptides in the dentate gyrus. Although we previously reported that large-conductance calcium-activated potassium (BK) channels are suppressed in 3xTg mice and their recovery relates to cognitive amelioration, no changes occurred by hybridization. Sphingomyelin in the membrane raft may serve as a novel target for AD drugs.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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