Abstract
Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.
Highlights
Alzheimer’s disease (AD) is clinically marked by memory disturbances followed by aphasia, apraxia, and agnosia and is later associated with behavioral symptoms [1].Neuropathological lesions include extracellular amyloid plaques made of aggregated amyloid-beta peptides including Aβ1-42 and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, neuroinflammation, and synaptic and neuronal loss [2].The causes of AD are unknown
Recent advances in cerebrospinal fluid (CSF), blood, and imaging biomarker research have demonstrated that Aβ1-42 accumulation starts decades before the first clinical sign, marked by reduced CSF levels, rapidly followed by CSF tau anomalies, and CSF triggering receptor expressed on myeloid cells 2 (TREM2) and neurogranin disturbances [5]
Pharmacological research is focusing on PKR and MAP kinase-activated protein kinase 2 (MK2) inhibitors which could interfere with abnormal brain signals detected in AD brains
Summary
Alzheimer’s disease (AD) is clinically marked by memory disturbances followed by aphasia, apraxia, and agnosia and is later associated with behavioral symptoms [1]. Recent advances in cerebrospinal fluid (CSF), blood, and imaging biomarker research have demonstrated that Aβ1-42 accumulation starts decades before the first clinical sign, marked by reduced CSF levels, rapidly followed by CSF tau anomalies, and CSF triggering receptor expressed on myeloid cells 2 (TREM2) and neurogranin disturbances [5]. The goal of the present review is to analyze the involvement of a specific signaling pathway in AD, starting with the cellular triggering of the eukaryotic initiation factor 2 α (eIF2α) kinase II (PKR) in brain cells and leading to the final activation of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1). PKR is implicated in many physiological functions including viral protection, control of translation initiation, apoptosis and cell proliferation, innate immunity, and inflammation [17]. (RIPK1); receptor-interacting serine/threonine-protein kinase 3 (RIPK3); dual specificity mitogen-activated protein kinase kinase 6 (MKK6); MAP kinase-activated protein kinase 2 (MK2)
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