Receptor-Interacting Protein Kinase 1 (RIPK1) as a Potential Therapeutic Target: An Overview of Its Possible Role in the Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer’s Disease (AD) is an age-dependent neurodegenerative disorder, the most common type of dementia that is clinically characterized by the presence of beta-amyloid (Aβ) extracellularly and intraneuronal tau protein tangles that eventually leads to the onset of memory and cognition impairment, development of psychiatric symptoms and behavioral disorders that affect basic daily activities. Current treatment approved by the U.S Food and Drug Administration (FDA) for AD is mainly focused on the symptoms but not on the pathogenesis of the disease. Recently, receptor-interacting protein kinase 1 (RIPK1) has been identified as a key component in the pathogenesis of AD through necroptosis. Furthermore, genetic and pharmacological suppression of RIPK1 has been shown to revert the phenotype of AD and its mediating pathway is yet to be deciphered. This review is aimed to provide an overview of the pathogenesis and current treatment of AD with the involvement of autophagy as well as providing a novel insight into RIPK1 in reverting the progression of AD, probably through an autophagy machinery.

Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

“…4 The marketed drugs are mainly focused on alleviating symptoms, including cholinesterase inhibitors and N-methyl-D-aspartate receptor noncompetitive antagonists. 5,6 Therefore, there is an urgent need to understand the basic molecular mechanisms underlying the neurodegenerative process in AD, providing cues to develop new therapeutics.…”

“…The neuropathological hallmarks of AD include amyloid angiopathy, marked neuroinflammation, deposition of extracellular beta-amyloid (Aβ), and loss of intracellular neurofibrillary tangles (NFTs), neurites, and synapses. , However, its exact pathogenic mechanism remains elusive and many hypotheses have been proposed including the amyloid cascade hypothesis, the Tau protein hypothesis, the metal ion hypothesis, the inflammation hypothesis, and the oxidative stress hypothesis . The marketed drugs are mainly focused on alleviating symptoms, including cholinesterase inhibitors and N -methyl- d -aspartate receptor noncompetitive antagonists. , Therefore, there is an urgent need to understand the basic molecular mechanisms underlying the neurodegenerative process in AD, providing cues to develop new therapeutics.…”

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

“…At present, whether TNF-α mediates pain-associated cognitive deficits by activating necroptosis remains unclear; however, its role has been reported in other neurodegenerative diseases. For example, necroptosis mediates TNF-α-induced toxicity of hippocampal neurons [231], leading to memory impairment in AD [159,232,233]. Inhibiting necroptosis and abnormally high expression of TNF-α in the hippocampus can reduce cell death and improve cognitive ability [159,[234][235][236].…”

Radiosynthesis and Evaluation of Cyclohexyl (5-(2-[11C-Carbonyl]acetamidobenzo[d]thiazol-6-yl)-2-Methylpyridin-3-yl)Carbamate ([11C]PK68) As a New Radioligand For Imaging Receptor-Interacting Protein 1 Kinase

“…Receptor-interacting protein 1 kinase (RIPK1) is a key regulator of neuronal death and is involved in apoptosis and necroptosis; it is related to several disorders including neuroin ammation, neurodegeneration, and carcinogenesis (Chan et al 2019;DeRoo et al 2020;Yu et al 2021;Yuan et al 2019). RIPK1 is a member of the RIP kinase family and contains a Ser/Thr kinase domain N-terminal, an intermediate domain, and a death domain C-terminal (Sunde et al 1997;Zhang et al 2018a).…”