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    • br Introduction Alzheimer s disease AD

    2020-03-30


    Introduction Alzheimer’s disease (AD) is the progressive version of mild cognitive impairment and usually met by the elderly population. It falls into the class of neurodegenerative disorders that attacks the tolbutamide synthesis nerves cells, or neurons, resulting in loss of memory, impairment of thinking and language skills, and causes behavioral changes. It is a progressive disorder which develops slowly and gets worse as the brain function declines. The brain cells eventually wither and die. Although 90% of cases of AD are sporadic, 5–10% are of familial AD (FAD) which has an early onset in an autosomal dominant pattern (Liu et al., 2016). The sporadic late onset AD (LOAD) on other hand commences in the age of 70s or 80s (Onos et al., 2016). Worldwide nearly 44 million people have Alzheimer’s disease. From the 5.1 million people of age 65 and older affected in 2015, the number is estimated to reach 7.1 million by 2025. Every 1 in 8 people over the age of 65 while, nearly half over the age of 85 have Alzheimer’s disease.
    Pathophysiology of AD
    Different protein kinase signalling pathways involved in AD
    Cdk5 as a therapeutic target Cyclin dependent kinase 5 (Cdk5) is a proline directed serine/threonine kinase. Functionally, Cdk5 plays an important role in neuron development, neuronal survival, phosphorylation of cytoskeletal proteins and synaptic plasticity (Mushtaq et al., 2016). Activation of Cdk5 requires regulatory proteins. In mammals, p35 and p39 are the two known proteins to activate Cdk5. These are specifically expressed in neuronal cells (Li et al., 2016). Increase in calcium concentration results in their calpain mediated cleavage into truncated products p25 and p29 respectively. Out of these, p35 is been extensively studied (Shukla et al., 2012). It can be split into 2 parts: p10 and p25 (Shukla et al., 2012). The N-terminal p10 region consists of the myristoylated region important for membrane targeting of p35 and the signal for degradation via ubiquitin-proteosome pathway (Wilkaniec et al., 2016). p25 has the Cdk5 binding as well as activation domain. It has been revealed from studies that Cdk5 kinase activity and substrate specificity is also regulated by phosphorylation and S-nitrosylation in addition to that by binding with its activators. Cdk5 has been shown to have three phosphorylation sites namely, Thr14, Tyr15, and Ser159 (Liu et al., 2016). The inhibition of Cdk5 is exhibited by phosphorylation at Thr14 while phosphorylation at Ser159 results in increased Cdk5 activation (Lee et al., 2014). Some of the previous studies demonstrated that phosphorylation at Tyr15 elevates Cdk5 activity whereas data from a recent study showed that the outcome from phosphorylation of Cdk5 at Tyr-15 does not activate Cdk5 (Lee et al., 2014, Kobayashi et al., 2014). Direct phosphorylation at p35 amino acid residues Ser8 and Thr138 by Cdk5 itself leads to inhibition of its activity (Shah and Lahiri, 2014) A novel regulatory mechanism for Cdk5 activity recently identified was S nitrosylation (SNO-Cdk5) at specific cysteine residues (Qu et al., 2012). S-nitrosothiol (SNO) is the product of the reaction between cysteine moiety and N2O3 (Tramutola et al., 2016). Nitric oxide is known to contribute to a number of neurodegenerative diseases such as AD, PD and HD (Qu et al., 2012). In neurons, NOS1 (neuronal nitric oxide synthase) is accountable for the synthesis of NO. NO appears to play crucial roles in dysfunction of mitochondria, protein misfolding, loss of synapse, and neuronal cell death (Ben Aissa et al., 2016). Increase in neuronal Ca2+ as well as Ca2+-binding protein calmodulin levels, leads to the activation of Nitric oxide synthase 1 (NOS1) and subsequent generation of NO from the amino acid l-arginine (Förstermann and Sessa, 2012). The N terminal of NOS1 comprises of the PDZ domain which couples to postsynaptic density protein (PSD)-95 and a variety of ion channels, including the NMDAR (Kim and Sheng, 2004). Therefore, NMDAR activation can be one of the pathways of activation of NOS1 in response to increased intracellular Ca2+ concentration (Qu et al., 2012). Cdk5’s kinase activity is activated by its S-nitrosylation at cysteine residues 83 and 157 (Qu et al., 2011). This triggers an increase in phosphorylated proteins namely, ataxia telangiectasia mutated (ATM) and pro-apoptotic serine/threonine-specific protein kinase (Kim et al., 2006, Tian et al., 2009). Synaptic failure due to SNO-CDK5 might occur via transfer of the NO group to Drp1, the reaction known as transnitrosylation. S-nitrosylated Drp1 stimulates excessive mitochondrial fission, which is associated with bioenergetic damage in the synapses, contributing to dendritic spine loss (Cho et al., 2009). These findings indicate that Cdk5 enzyme may possess dual function of phosphorylation as well as transnitrosylation (Qu et al., 2012). Pharmacological actions associated with Cdk5 are summarized in Table 1.