Biology Department, College of Science and Humanities, Shaqra University, Saudi Arabia.
Department of Biology, Jamoum University College, Umm Al-Qura University, 21955 Makkah, Saudi Arabia.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167353. doi: 10.1016/j.bbadis.2024.167353. Epub 2024 Jul 14.
The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD).
Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology.
Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A) mice revealed that Gadd45A mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A mice, likely contributing to the observed cognitive deficits.
These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.
生长停滞和 DNA 损伤诱导 45（Gadd45）基因已被牵涉到各种中枢神经系统（CNS）的功能，包括正常和病理的，包括衰老、记忆和神经退行性疾病。在这项研究中，我们检查了 Gadd45A 的缺失是否会引发与神经退行性疾病相关的途径，包括阿尔茨海默病（AD）。
利用与 AD 相关的海马体样本的转录组数据，我们发现 Gadd45A 是自噬的关键调节因子。综合分析，包括基因本体富集和蛋白质-蛋白质相互作用网络评估，突出了 Cdkn1A 作为 Gadd45A 的一个重要下游靶点。实验验证证实了 Gadd45A 在调节海马细胞中 Cdkn1A 表达和自噬水平方面的作用。我们还研究了自噬对海马功能和促炎细胞因子分泌的影响。此外，还使用了小鼠模型来验证 Gadd45A 在神经炎症和 AD 病理学中的重要性。
我们的研究确定了 20 个与 AD 相关的自噬调节因子，其中 Gadd45A 是一个关键的调节因子。实验结果表明，Gadd45A 通过降低 Cdkn1A 表达和抑制自噬活性来影响海马细胞的命运。野生型（WT）和 Gadd45A 敲除（Gadd45A）小鼠之间的比较表明，Gadd45A 小鼠表现出明显的认知障碍，包括工作记忆和空间记忆缺陷、Tau 过度磷酸化增加以及海马中参与 Tau 磷酸化的激酶水平升高。此外，Gadd45A 小鼠的促炎细胞因子水平显著升高，大脑中的自噬标志物水平降低。Gadd45A 小鼠的神经营养因子水平和树突棘长度也降低，这可能导致观察到的认知缺陷。
这些发现支持 Gadd45A 基因直接参与 AD 发病机制，增强 Gadd45A 的表达可能代表治疗 AD 的一种有前途的治疗策略。
