Cyclin‐Dependent kinase 5 targeting prevents β‐Amyloid aggregation involving glycogen synthase kinase 3β and phosphatases

Abstract

Inappropriate activation of CDK5 due to proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles, β-amyloid aggregation and chronic neurodegeneration. At 18 months of age, 3xTg-AD mice were sacrificed after either three weeks (short-term) or one year (long-term) of CDK5 knockdown. In short-term-treated animals, CDK5 knockdown reversed β-amyloid aggregation in the hippocampi via inhibitory phosphorylation of GSK3β Ser 9 and activation of phosphatase PP2A. In long-term-treated animals, CDK5 knockdown induced a persistent reduction in CDK5 and prevented β-amyloid aggregation, but the effect on APP processing was reduced, suggesting that yearly booster therapy would be necessary. These findings further validate CDK5 as a target for preventing or blocking amyloidosis in older transgenic mice.

Selenomethionine Ameliorates Neuropathology in the Olfactory Bulb of a Triple Transgenic Mouse Model of Alzheimer’s Disease

“…This overactivation of CDK5 resulted in the hyperphosphorylation of tau protein at different sites (such as Ser199 and 202, Thr205, 212, and 231, Ser235, 396, and 404), thereby resulting in PHF (paired helical filaments) formation and the subsequent formation of NFTs [37,38]. CDK5 knockdown reversed Aβ aggregation in the hippocampus by inhibiting the phosphorylation of GSK-3β at Ser9 and activating PP2A [39,40]. Interestingly, Se-Met could significantly decrease the expression of CDK5 in the OB.…”

Regulation of Axonal Transport by Protein Kinases

“…However, unlike other cyclin-dependent kinases, Cdk5 does not play a direct role in cell cycle control. Instead, Cdk5 regulates several processes in the nervous system, including neurite outgrowth, synaptic activity, and neuronal migration [12], and its deregulation has been linked to neurodegeneration [67,68].…”

Dementia, Preclinical Studies in Neurodegeneration and its Potential for Translational Medicine in South America

“…Interestingly, silenced BACE1 (main enzyme involved in the production of βA), in the hippocampus using adenoassociated viral vectors reduces the hyperphosphorilation of tau (Piedrahita et al, 2016) and improve cognitive function at 6 months and 12 months post-treatment, presenting a balanced phospholipid composition, by the reduction of saturated fatty acid (stearic acid (18:0), palmitic acid (16:0)) and increase of poli-unsaturated fatty acid (docosahexaenoic acid, DHA (22:6)), which prevented the activation of pro-inflammatory signaling cPLA2/AA/COX2 in old AD mice to long-term post-therapy (Villamil-Ortiz et al, 2016). Also, the silencing of CDK5 in the CA1 hippocampal area prevents the spreading of excitoxicity to other areas of the neuronal circuit (Piedrahita et al, 2010; Castro-Alvarez et al, 2014, 2015; Posada-Duque et al, 2015a) also reversing (Piedrahita et al, 2010) or preventing neurodegeneration by reduction of paired helicoidal formations (Castro-Alvarez et al, 2014) and further, decreases the β amyloidosis production (Castro-Alvarez et al, 2015). The result could be assumed as it involves the prevention of Calpain activation by reduction of the active p25/CDK5 complex formation (Posada-Duque et al, 2015a) with a clear impact on the down-regulation of phosphorilation rate of tau (Castro-Alvarez et al, 2015), as well as regulation of phosphatases and GSK3β activity (Castro-Alvarez et al, 2015).…”

“…Also, the silencing of CDK5 in the CA1 hippocampal area prevents the spreading of excitoxicity to other areas of the neuronal circuit (Piedrahita et al, 2010; Castro-Alvarez et al, 2014, 2015; Posada-Duque et al, 2015a) also reversing (Piedrahita et al, 2010) or preventing neurodegeneration by reduction of paired helicoidal formations (Castro-Alvarez et al, 2014) and further, decreases the β amyloidosis production (Castro-Alvarez et al, 2015). The result could be assumed as it involves the prevention of Calpain activation by reduction of the active p25/CDK5 complex formation (Posada-Duque et al, 2015a) with a clear impact on the down-regulation of phosphorilation rate of tau (Castro-Alvarez et al, 2015), as well as regulation of phosphatases and GSK3β activity (Castro-Alvarez et al, 2015). All of this, would lead to the control of both histopathological hallmarks, improving the neurotransmission and synaptic remodeling (Posada-Duque et al, 2016); at the same time recovering the complex synaptic molecular adhesion (p120 ctn/PSD95), which has a consequential long-term effect (12 months) in protection and improvement of cognitive function (Castro-Alvarez et al, 2015; Uribe-Arias et al, 2016).…”

“…The result could be assumed as it involves the prevention of Calpain activation by reduction of the active p25/CDK5 complex formation (Posada-Duque et al, 2015a) with a clear impact on the down-regulation of phosphorilation rate of tau (Castro-Alvarez et al, 2015), as well as regulation of phosphatases and GSK3β activity (Castro-Alvarez et al, 2015). All of this, would lead to the control of both histopathological hallmarks, improving the neurotransmission and synaptic remodeling (Posada-Duque et al, 2016); at the same time recovering the complex synaptic molecular adhesion (p120 ctn/PSD95), which has a consequential long-term effect (12 months) in protection and improvement of cognitive function (Castro-Alvarez et al, 2015; Uribe-Arias et al, 2016). Therefore, safe and effective studies suggest that the BACE1 and CDK5 RNAi-based therapy would be ready for a potential translational trial in a patient with advanced or mild stage of Alzheimer disease, without additional option for a curative treatment.…”