Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of Aβ peptides, hyperphosphorylated tau proteins, and neuronal loss in the brain of affected patients. The causes of neurodegeneration in AD are not clear, but apoptosis could be one of the cell death mechanisms. According to the amyloid hypothesis, abnormal aggregation of Aβ leads to altered kinase activities inducing tau phosphorylation and neuronal degeneration. Several studies have shown that pro-apoptotic kinases could be a link between Aβ and tau anomalies. Here, we present recent evidences from AD experimental models and human studies that three pro-apoptotic kinases (double-stranded RNA kinase (PKR), glycogen synthase kinase-3β, and C-Jun terminal kinase (JNK) could be implicated in AD physiopathology. These kinases are detectable in human fluids and the analysis of their levels could be used as potential surrogate markers to evaluate cell death and clinical prognosis. In addition to current biomarkers (Aβ1–42, tau, and phosphorylated tau), these new evaluations could bring about valuable information on potential innovative therapeutic targets to alter the clinical evolution.
Highlights
Neuropathological lesions in Alzheimer’s disease (AD) include senile plaques, neurofibrillary tangles, and amyloid angiopathy leading to synaptic and neuronal degradations
Using animal and cells models, we have shown that PKR is activated by Aβ peptide [8, 53, 55,56,57,58,59,60,61] through its activator PACT [56], and this activation plays a role in neuronal death in AD [8, 55, 56], we have shown that the activation of PKR could control the levels of β-secretase (BACE1) in stressed cells
The concentrations of total PKR (T-PKR) and pro-apoptotic forms of PKR (pPKR) were significantly increased in AD patients and in most mild cognitive impairment (MCI) patients compared to neurological controls
Summary
Neuropathological lesions in Alzheimer’s disease (AD) include senile plaques, neurofibrillary tangles, and amyloid angiopathy leading to synaptic and neuronal degradations. Activated and pro-apoptotic forms of PKR (pPKR) can accumulate in several neurodegenerative diseases including AD [9, 12, 52,53,54]. Aβ induced the phosphorylation of PKR, glycogen synthase kinase-3β (GSK-3β), and tau. The pharmacological inhibition of PKR reduced GSK-3 activation and tau phosphorylation, suggesting that PKR could indirectly control the abnormal formation of tangles [8].
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