Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, 151401, India.
Apoptosis. 2023 Aug;28(7-8):943-957. doi: 10.1007/s10495-023-01848-y. Epub 2023 Apr 26.
Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and amyloid-β (Aβ) protein resulting in synaptic loss and apoptosis. Aβ and tau deposition trigger apoptotic pathways that result in neuronal death. Apoptosis is considered to be responsible for manifestations associated with AD under pathological conditions. It regulates via extrinsic and intrinsic pathways. It activates various proteins including Bcl-2 family proteins like Bax, Bad, Bid, Bcl-XS, Bcl-XL and caspases comprising of initiator, effector and inflammatory caspases carried out through a cascade of events that finally lead to cell disintegration. The apoptotic elements interact with trophic factors, signaling molecules including Ras-ERK, JNK, GSK-3β, BDNF/TrkB/CREB and PI3K/AKT/mTOR. Ras-ERK signaling is involved in the progression of cell cycle and apoptosis. JNK pathway is also upregulated in AD which results in decreased expression of anti-apoptotic proteins. JAK-STAT triggers caspase-3 mediated apoptosis leading to neurodegeneration. The imbalance between autophagy and apoptosis is regulated by PI3K/Akt/mTOR pathway. GSK-3β is involved in the stimulation of pro-apoptotic factors resulting in dysregulation of apoptosis. Drugs like filgrastim, epigallocatechin gallate, curcumin, nicergoline and minocycline are under development which target these pathways and modulate the disease condition. This study sheds light on apoptotic pathways that are cardinal for neuronal survival and perform crucial role in the occurrence of AD along with the trends in therapeutics targeting apoptosis induced AD. To develop prospective treatments for AD, it is desirable to elucidate potential targets including restoration apoptotic balance, regulation of caspases, Bcl-2 and other crucial proteins involved in apoptosis mediated AD.
阿尔茨海默病(AD)的特征是过度磷酸化的 tau 和淀粉样β(Aβ)蛋白的积累,导致突触丧失和细胞凋亡。Aβ和 tau 的沉积触发凋亡途径,导致神经元死亡。凋亡被认为是病理性 AD 相关表现的原因。它通过外在和内在途径进行调节。它激活各种蛋白质,包括 Bax、Bad、Bid、Bcl-XS、Bcl-XL 等 Bcl-2 家族蛋白和包含起始、效应和炎症半胱天冬酶的 caspase,通过一系列事件的级联反应最终导致细胞解体。凋亡元件与营养因子、信号分子相互作用,包括 Ras-ERK、JNK、GSK-3β、BDNF/TrkB/CREB 和 PI3K/AKT/mTOR。Ras-ERK 信号通路参与细胞周期和凋亡的进展。AD 中 JNK 途径也被上调,导致抗凋亡蛋白表达减少。JAK-STAT 触发 caspase-3 介导的凋亡导致神经退行性变。自噬和凋亡之间的失衡由 PI3K/Akt/mTOR 途径调节。GSK-3β参与促凋亡因子的刺激,导致凋亡失调。正在开发的药物,如非格司亭、表没食子儿茶素没食子酸酯、姜黄素、尼麦角林和米诺环素,针对这些途径并调节疾病状况。本研究阐明了对神经元存活至关重要的凋亡途径,并探讨了靶向 AD 诱导凋亡的治疗方法的发展趋势。为了开发 AD 的前瞻性治疗方法,阐明潜在靶点,包括恢复凋亡平衡、调节 caspase、Bcl-2 和其他参与凋亡介导的 AD 的关键蛋白,是非常有必要的。
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