Enhanced hippocampal TIAM2S expression alleviates cognitive deficits in Alzheimer's disease model mice.

Autor: Sung KC; Department of Neurosurgery, Chi-Mei Medical Center, 901 Chung Hwa Road, Yung Kang City, Tainan, Taiwan., Wang LY; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan., Wang CC; Department of Neurosurgery, Chi-Mei Medical Center, 901 Chung Hwa Road, Yung Kang City, Tainan, Taiwan., Chu CH; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Sun HS; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Hsiao YH; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. yahsin@mail.ncku.edu.tw.; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. yahsin@mail.ncku.edu.tw.
Jazyk: angličtina
Zdroj: Pharmacological reports : PR [Pharmacol Rep] 2024 Oct; Vol. 76 (5), pp. 1032-1043. Date of Electronic Publication: 2024 Jul 16.
DOI: 10.1007/s43440-024-00623-3
Abstrakt: Background: Dendritic spine dysfunction is a key feature of Alzheimer's disease (AD) pathogenesis. Human T-cell lymphoma invasion and metastasis 2 (TIAM2) is expressed in two isoforms, the full length (TIAM2L) and a short transcript (TIAM2S). Compared to TIAM2L protein, which is undetectable, TIAM2S protein is abundant in human brain tissue, especially the hippocampus, and can promote neurite outgrowth in our previous findings. However, whether enhanced hippocampal TIAM2S expression can alleviate cognitive deficits in Alzheimer's disease model mice remains unclear.
Methods: We crossbred 3xTg-AD with TIAM2S mice to generate an AD mouse model that carries the human TIAM2S gene (3xTg-AD/TIAM2S mice). The Morris water maze and object location tests assessed hippocampus-dependent spatial memory. Lentiviral-driven shRNA or cDNA approaches were used to manipulate hippocampal TIAM2S expression. Golgi staining and Sholl analysis were utilized to measure neuronal dendrites and dendritic spines in the mouse hippocampi.
Results: Compared to 3xTg-AD mice, 3xTg-AD/TIAM2S mice displayed improved cognitive functions. According to the hippocampus is one of the earliest affected brain regions by AD, we further injected TIAM2S shRNA or TIAM2S cDNA into mouse hippocampi to confirm whether manipulating hippocampal TIAM2S expression could affect AD-related cognitive functions. The results showed that the reduced hippocampal TIAM2S expression in 3xTg-AD/TIAM2S mice abolished the memory improvement effect, whereas increased hippocampal TIAM2S levels alleviated cognitive deficits in 3xTg-AD mice. Furthermore, we found that TIAM2S-mediated memory improvement was achieved by regulating dendritic plasticity.
Conclusions: These results will provide new insights into connecting TIAM2S with AD and support the notion that TIAM2S should be investigated as potential AD therapeutic targets.
(© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)
Databáze: MEDLINE
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