Scholarlink

<p>Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition, chronic neuroinflammation, and dysregulation of the cAMP/PKA/CREB pathway that impairs synaptic plasticity. PF-04957325 (PF), a selective PDE8B inhibitor, elevates intracellular cAMP; however, its systems-level effects and mechanisms in Aβ-driven AD are unclear. Here, we evaluate PF in an Aβ1–42 mouse model and delineate its modulation of cAMP/PKA/CREB and TLR4/MyD88/NF-κB signaling.&#xa0;An AD model was induced by intracerebroventricular injection of Aβ1–42, followed by oral PF administration (0.1&#xa0;mg/kg/day). Cognitive performance was evaluated with the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were assessed by H&amp;E, immunohistochemistry, and TUNEL assays. IL-1β and IL-6 were measured by ELISA in hippocampal tissue and BV2 supernatants. Western blotting quantified APP, p-tau, and pathway proteins. BV2 cells and si-PDE8B served to validate mechanisms in vitro.&#xa0;PF significantly shortened escape latency (<i>p</i> &lt; 0.01) and increased both platform crossings and target-quadrant dwell time (<i>p</i> &lt; 0.01). It alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive cells. Molecularly, PF elevated cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (<i>p</i> &lt; 0.01), while decreasing TLR4, MyD88, and p-NF-κB p65/NF-κB p65 (<i>p</i> &lt; 0.01). PF also lowered IL-1β and IL-6 levels in hippocampal tissue and BV2 supernatants (both <i>p</i> &lt; 0.01). In vitro, 300 nM PF phenocopied PDE8B knockdown, restoring cAMP/PKA/CREB activity and suppressing TLR4/MyD88/NF-κB activation.&#xa0;PF exerts dual protective effects by activating cAMP/PKA/CREB to enhance synaptic plasticity and survival, while inhibiting TLR4/MyD88/NF-κB to mitigate neuroinflammation. These findings highlight PDE8B inhibition as a promising therapeutic strategy for AD.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Regulatory Effects of the PDE8B Inhibitor PF-04957325 on Cognitive Impairment and Neuroinflammation in Aβ-Induced Alzheimer’s Disease Mouse Models

  • 期刊论文

  • 发表日期：

    2026年7月9日

查看全文
  • YaQun Liu,
  • MuYang Li,
  • HongBo Yu,
  • HuiYing Liu,
  • QiuShuang Xu,
  • Fang Li

摘要

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition, chronic neuroinflammation, and dysregulation of the cAMP/PKA/CREB pathway that impairs synaptic plasticity. PF-04957325 (PF), a selective PDE8B inhibitor, elevates intracellular cAMP; however, its systems-level effects and mechanisms in Aβ-driven AD are unclear. Here, we evaluate PF in an Aβ1–42 mouse model and delineate its modulation of cAMP/PKA/CREB and TLR4/MyD88/NF-κB signaling. An AD model was induced by intracerebroventricular injection of Aβ1–42, followed by oral PF administration (0.1 mg/kg/day). Cognitive performance was evaluated with the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were assessed by H&E, immunohistochemistry, and TUNEL assays. IL-1β and IL-6 were measured by ELISA in hippocampal tissue and BV2 supernatants. Western blotting quantified APP, p-tau, and pathway proteins. BV2 cells and si-PDE8B served to validate mechanisms in vitro. PF significantly shortened escape latency (p < 0.01) and increased both platform crossings and target-quadrant dwell time (p < 0.01). It alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive cells. Molecularly, PF elevated cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (p < 0.01), while decreasing TLR4, MyD88, and p-NF-κB p65/NF-κB p65 (p < 0.01). PF also lowered IL-1β and IL-6 levels in hippocampal tissue and BV2 supernatants (both p < 0.01). In vitro, 300 nM PF phenocopied PDE8B knockdown, restoring cAMP/PKA/CREB activity and suppressing TLR4/MyD88/NF-κB activation. PF exerts dual protective effects by activating cAMP/PKA/CREB to enhance synaptic plasticity and survival, while inhibiting TLR4/MyD88/NF-κB to mitigate neuroinflammation. These findings highlight PDE8B inhibition as a promising therapeutic strategy for AD.