Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South 4Th Ring West Road, Fengtai District, Beijing, 100070, China.
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Alzheimers Res Ther. 2023 Oct 27;15(1):184. doi: 10.1186/s13195-023-01334-2.
Autophagy is vital in the pathogenesis of neurodegeneration. Thus far, no studies have specifically investigated the relationship between pituitary adenylate cyclase-activating polypeptide (PACAP) and autophagy, particularly in the context of Alzheimer's disease (AD). This study used in vitro and in vivo models, along with clinical samples, to explore interactions between PACAP and autophagy in AD.
AD model mice were administered 6 μl of 0.1 mg/ml PACAP liquid intranasally for 4 weeks, then subjected to behavioral analyses to assess the benefits of PACAP treatment. The underlying mechanisms of PACAP-induced effects were investigated by methods including real-time quantitative polymerase chain reaction, RNA sequencing, immunofluorescence, and western blotting. Exosomes were extracted from human serum and subjected to enzyme-linked immunosorbent assays to examine autophagy pathways. The clinical and therapeutic implications of PACAP and autophagy were extensively investigated throughout the experiment.
Impaired autophagy was a critical step in amyloid β (Aβ) and Tau deposition; PACAP enhanced autophagy and attenuated cognitive impairment. RNA sequencing revealed three pathways that may be involved in AD progression: PI3K-AKT, mTOR, and AMPK. In vivo and in vitro studies showed that sirtuin3 knockdown diminished the ability of PACAP to restore normal autophagy function, resulting in phagocytosis dysregulation and the accumulation of pTau, Tau, and Aβ. Additionally, the autophagic biomarker MAP1LC3 demonstrated a positive association with PACAP in human serum.
PACAP reverses AD-induced cognitive impairment through autophagy, using sirtuin3 as a key mediator. MAP1LC3 has a positive relationship with PACAP in humans. These findings provide insights regarding potential uses of intranasal PACAP and sirtuin3 agonists in AD treatment.
NCT04320368.
自噬在神经退行性变的发病机制中至关重要。迄今为止，尚无研究专门探讨垂体腺苷酸环化酶激活肽（PACAP）与自噬之间的关系，特别是在阿尔茨海默病（AD）的背景下。本研究使用体外和体内模型以及临床样本，探讨了 AD 中 PACAP 与自噬之间的相互作用。
AD 模型小鼠经鼻内给予 6 μl 0.1mg/ml PACAP 液，共 4 周，然后进行行为分析，以评估 PACAP 治疗的益处。通过实时定量聚合酶链反应、RNA 测序、免疫荧光和 Western blot 等方法研究 PACAP 诱导作用的潜在机制。从人血清中提取外泌体，并进行酶联免疫吸附试验，以检测自噬途径。在整个实验过程中，广泛研究了 PACAP 和自噬的临床和治疗意义。
自噬受损是淀粉样β（Aβ）和 Tau 沉积的关键步骤；PACAP 增强自噬并减轻认知障碍。RNA 测序显示，有 3 条途径可能参与 AD 进展：PI3K-AKT、mTOR 和 AMPK。体内和体外研究表明，沉默 Sirtuin3 会降低 PACAP 恢复正常自噬功能的能力，导致吞噬作用失调以及 pTau、Tau 和 Aβ 的积累。此外，自噬生物标志物 MAP1LC3 在人血清中与 PACAP 呈正相关。
PACAP 通过 Sirtuin3 作为关键介质，通过自噬逆转 AD 引起的认知障碍。MAP1LC3 与人血清中的 PACAP 呈正相关。这些发现为鼻内 PACAP 和 Sirtuin3 激动剂在 AD 治疗中的潜在用途提供了思路。
NCT04320368。
