Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China.
Key Laboratory of Atherosclerosis, University of Shandong, Jinan, China.
J Alzheimers Dis. 2021;82(4):1635-1649. doi: 10.3233/JAD-210463.
Phospholipid transfer protein (PLTP) belongs to the lipid transfer glycoprotein family. Studies have shown that it is closely related to Alzheimer's disease (AD); however, the exact effect and mechanism remain unknown.
To observe the effect of PLTP overexpression on behavioral dysfunction and the related mechanisms in APP/PS1/Tau triple transgenic (3×Tg-AD) mice.
AAV-PLTP-EGFP was injected into the lateral ventricle to induce PLTP overexpression. The memory of 3×Tg-AD mice and wild type (WT) mice aged 10 months were assessed using Morris water maze (MWM) and shuttle-box passive avoidance test (PAT). Western blotting and ELISA assays were used to quantify the protein contents. Hematoxylin and eosin, Nissl, and immunochemistry staining were utilized in observing the pathological changes in the brain.
3×Tg-AD mice displayed cognitive impairment in WMW and PAT, which was ameliorated by PLTP overexpression. The histopathological hallmarks of AD, senile plaques and neurofibrillary tangles, were observed in 3×Tg-AD mice and were improved by PLTP overexpression. Besides, the increase of amyloid-β42 (Aβ42) and Aβ40 were found in the cerebral cortex and hippocampus of 3×Tg-AD mice and reversed by PLTP overexpression through inhibiting APP and PS1. PLTP overexpression also reversed tau phosphorylation at the Ser404, Thr231 and Ser199 of the hippocampus in 3×Tg-AD mice. Furthermore, PLTP overexpression induced the glycogen synthase kinase 3β (GSK3β) inactivation via upregulating GSK3β (pSer9).
These results suggest that PLTP overexpression has neuroprotective effects. These effects are possibly achieved through the inhibition of the Aβ production and tau phosphorylation, which is related to GSK3β inactivation.
磷脂转运蛋白（PLTP）属于脂质转运糖蛋白家族。研究表明，它与阿尔茨海默病（AD）密切相关，但确切的作用和机制尚不清楚。
观察 PLTP 过表达对 APP/PS1/Tau 三转基因（3×Tg-AD）小鼠行为功能障碍的影响及其相关机制。
通过立体定位侧脑室注射 AAV-PLTP-EGFP 诱导 PLTP 过表达。采用 Morris 水迷宫（MWM）和穿梭箱被动回避试验（PAT）评估 10 月龄 3×Tg-AD 小鼠和野生型（WT）小鼠的记忆能力。Western blot 和 ELISA 检测用于定量蛋白质含量。苏木精-伊红、尼氏和免疫组织化学染色用于观察脑内的病理变化。
3×Tg-AD 小鼠在 MWM 和 PAT 中表现出认知障碍，而过表达 PLTP 可改善这些认知障碍。在 3×Tg-AD 小鼠中观察到 AD 的组织病理学特征，即老年斑和神经纤维缠结，并通过过表达 PLTP 得到改善。此外，在 3×Tg-AD 小鼠的大脑皮质和海马区发现 Aβ42（Aβ42）和 Aβ40 增加，而过表达 PLTP 可通过抑制 APP 和 PS1 逆转这种增加。PLTP 过表达还可逆转 3×Tg-AD 小鼠海马区 tau 丝氨酸 404、苏氨酸 231 和丝氨酸 199 的磷酸化。此外，PLTP 过表达通过上调 GSK3β（pSer9）诱导糖原合酶激酶 3β（GSK3β）失活。
这些结果表明 PLTP 过表达具有神经保护作用。这些作用可能是通过抑制 Aβ 生成和 tau 磷酸化来实现的，而这与 GSK3β 失活有关。
