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  • br Deregulation of CDK Many neurotoxic or


    Deregulation of CDK5 Many neurotoxic or stress conditions like ischemic Silydianin synthesis damage, oxidative stress, mitochondrial dysfunctions, excitotoxicity, Aβ exposure lead to disruption of the tight regulation of Cdk5 (De Strooper et al., 2010). Calpain-mediated cleavage of p35 to p25 is activated under high Ca2+ concentration, forming a more stable Cdk5/p25 complex (Lee et al., 2000). p25 can effectively activate Cdk5 both in vitro and in vivo as it contains the necessary activation sites (Patrick et al., 1999). A very long half-life and lack of the p10 domain makes p25 form a stronger and a stable association with Cdk5 and also localize to cell soma and nucleus. This hyperactive complex then causes hyperphosphorylation of tau and neurofilaments leading to neurodegeneration and cell death (Lee et al., 2000, Noble et al., 2003). The complex also stimulates oxidative stress and mitochondrial dysfunction (Sun et al., 2008a). Therefore, hyperactivity of Cdk5 is involved in promoting cell death via a feedback loop mechanism by being an upstream manager as well as a downstream effector of mitochondrial dysfunction (Sun et al., 2008a) (Fig. 2). Additionally, AD brains display a symbolic increase in Cdk5 activity along with an increase in p25 and p38 levels (Pei et al., 2001, Zhu et al., 2001).
    Role of Cdk5 in plaque formation In AD pathogenesis, the key component of amyloid plaques is the accumulation of amyloid-β peptide (Barucker et al., 2015, Mawuenyega et al., 2010). Aβ is formed due to the sequential cleaving of integral membrane glycoprotein APP by β-secretase (BACE1) succeeded by γ-secretase in the transmembrane region liberating Aβ peptides (Castrillo and Oliver, 2016). Due to the profusion of extracellular deposition of Aβ peptides, plaques are formed. APP is a substrate of Cdk5 (Su and Tsai, 2011). Cdk5 carries out the phosphorylation of APP at Thr668 which affects the binding of APP to the cytoplasmic adaptor protein Fe65, demonstrating that phosphorylation of APP at Thr668 plays an important role in normal functioning (Ando et al., 2001). There is an upregulation of this phosphorylation in large endocytic vesicles which are ample in AD brain tissues. Endocytic trafficking of APP due to Thr668 phosphorylation also leads to β- secretase cleavage of APP and increases the Aβ production (Liu et al., 2016). Both in vitro and in vivo studies have shown that levels of presenilin (PS1) are elevated due to phosphorylation of PS1 at Thr364 by Cdk5 (Lau et al., 2002). This is inevitably required for gamma secretase activity and Aβ catabolism (Lau et al., 2002). Hyperactivity of Cdk5 results in the formation of Aβ aggregates that induce neurotoxicity.
    Role of Cdk5 in neurofibrillary tangle formation Neurofibrillary Tangles comprising of hyperphosphorylated cytosketal proteins such as tau and neurofilaments is another pathological hallmark of AD. Cdk5 localization on NFT bearing neurons has been observed in immunohistochemical analysis of human brain (Yamaguchi et al., 1996). Pretangle neurons show increased Cdk5 immunoreactivity indicating involvement of Cdk5 during the early stage of the disease (Augustinack et al., 2002). The kinase activity of Cdk5 in phosphorylating tau is significantly higher in the presence of p25 compared to p35 (Kimura et al., 2014). Physiologically Cdk5 phosphorylates many epitopes of tau such as Ser202, Thr205, Ser235, and Ser404, which are hyperphosphorylated in AD (Kimura et al., 2014) Increased expression of Cdk5/p25 results in hyperphosphorylation of neurofilaments, which leads to impaired axonal transport (Zhou et al., 2010). Contribution of Cdk5/p25 to tau pathology and tangle formation makes it a prime therapeutic target for AD.
    Implications of deregulated Cdk5 on other pathways mediating AD
    CDK5/P25 inhibitors as therapeutic candidates
    Introduction One particular class of targeted agents that merits consideration is the cyclin dependent kinase (CDK) inhibitors. Cyclins, as might be guessed from the name, fluctuate with and are indispensible components of eukaryotic cell cycle, and the discovery of these proteins and their cyclic expression was instrumental in helping to understand and develop the model of the cell cycle [1]. Subsequent studies have shown that their regular rise and fall is critical to eukaryotic cell cycle progression, and that their orderly fluctuations are controlled by internal and external stimuli and anti-stimuli. Cyclins are actually components of a complex consisting of cyclins and CDKs; the cyclin subunit serves to activate the CDK (and by virtue of its variable level it is a de facto regulator of CDKs), while the CDK itself is the effector subunit [2]. CDKs act as serine/threonine protein kinases, which directly or indirectly activate factors integral to cell cycle. For example, CDK4 and CDK6 in cooperation with cyclin D inactivates retinoblastoma (Rb), in turn releasing the transcription factor E2F; the transcription factor is then free to awaken a number of genes important to mitosis [3]. Rb is among the most well known among the tumor-suppressor genes, and the potential importance of CDKs in cancer is readily apparent. Thinking along these lines, CDK inhibitors have been explored as a class of novel therapeutic agents with a goal to disrupt CDKs’ control of cell cycle.