Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision‐like Proteins?

Abstract

Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterized by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the embryonic lethal abnormal vision (ELAV)-like RNA-binding proteins that modulate the stability and the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD. Alzheimer's DiseaseAlzheimer's disease (AD) is a progressive neurodegenerative disorder, which leads to severe impairment of memory and cognitive functions, alterations in behaviour, incapacity for independent living and, finally, to death. It is the most common cause of dementia [1], which affects more than 35 million people worldwide [2]. The prevalence of both AD and dementia escalates along with increasing age. As the life span in developing countries rises, the number of people with dementia is expected to almost double every 20 years and reach 115 million in 2050 [2]. In the World Alzheimer Report 2013, it was estimated that in 2013, the global costs of dementia exceed US$600 billion, which is approximately 1% of global gross domestic product [3].The current pharmacological therapy for AD includes cholinesterase inhibitors (donepezil, rivastigmine and galantamine) as well as memantine, which is a low-affinity voltage-dependent uncompetitive antagonist of glutamatergic N-methyl-Daspartate (NMDA) receptors. Additionally, the neuropsychiatric symptoms are commonly treated with antidepressants and/or risperidone or other atypical antipsychotics. All of the available treatments are symptomatic and cannot cure or significantly inhibit the progression of the disease. Therefore, new disease-modifying treatments are urgently needed.The main neuropathological change characteristic to AD is the loss of cholinergic neurons in the nucleus basalis magnocellularis and their synapses, particularly in cerebral cortex, hippocampus and other subcortical structures that contribute to memory formation [4,5]. The underlying neuropathogenesis is not known, but the loss of neurons results from the accumulation of two distinctive pathological features: predominantly extracellular b amyloid (Ab) deposits (plaques) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau p...

Protein kinase C -activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations

“…Furthermore, the levels and activity of PKC isoforms is attenuated in the brain of AD patients (Lucke-Wold et al, 2015;Wang et al, 1994). In line with these observations, encouraging results on the effects of PKC activators in both in vitro and in vivo models of AD have been reported (Talman et al, 2016). Many of the positive effects induced by PKC activators have been attributed to the activation of isoforms ε and γ (Lucke-Wold et al, 2015), which has evoked ideas about specifically targeting these isoforms.…”

“…Dysregulation in PKC activation has been shown to associate with many pathophysiological features of AD, including memory loss, increased levels of Aβ and β-amyloid plaques, neurofibrillary tangles as well as neuroinflammation, and PKC activators have therefore been suggested to represent promising drug candidates for the treatment of AD (Alkon et al, 2007;Sun and Alkon, 2012). Furthermore, several PKC activators, such as DAG-lactones and bryostatins, have been shown to alleviate pathophysiological hallmarks of AD in both in vitro and in vivo models (reviewed in (Talman et al, 2016)). Here, we report for the first time the effects of PKC C1 domain ligands, 5-(hydroxymethyl) isophthalate derivatives HMI-1a3 and HMI-1b11 in different in vitro models of relevant for AD.…”

“…PKC has been called a "memory kinase" and it has been widely studied in relation to its central role in memory formation in both normal and pathological settings, such as AD models (Lucke-Wold et al, 2015). As PKC regulates several processes linked to AD pathophysiology, its pharmacological activation is considered a potential therapeutic strategy for treating AD (Alkon et al, 2007;Alkon, 2012, 2010;Talman et al, 2016). A number of studies have shown that PKC activation directs APP processing to the non-pathogenic α-secretase pathway and thereby increases the production of neuroprotective sAPPα and reduces the production of neurotoxic Aβ species both in vitro and in vivo (Alkon et al, 2007;Buxbaum et al, 1990;Etcheberrigaray et al, 2004;Jacobsen et al, 1994;Kozikowski et al, 2003).…”

“…Pharmacological PKC activation can be achieved by targeting its regulatory C1 domain, which is also the binding site for the physiological activator DAG. Several families of C1 domain-targeting PKC agonists, such as phorbol esters, bryostatins, DAG lactones and benzolactams, have been described and investigated in the in vitro and in vivo models of AD (Boije af Gennäs et al, 2011;Talman et al, 2016). Most PKC activators are however scarce in natural sources and highly complex in their chemical structure, making them expensive to isolate in sufficient quantities and difficult to synthesize.…”

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

“…Those signaling transduction pathways play critical roles in modulating the functional status of several SV and synaptic plasma membrane proteins via phosphorylation, thus potentiating presynaptic activity. In fact, deregulated activities of CaMKII [112–115], PKA [116, 117], and PKC [118, 119] have been repeatedly linked to compromised synaptic activity and neuronal death in AD. The dysfunction of these transduction pathways is at least in part associated with calcium dysmetabolism, ATP deficiency, and oxidative stress in AD neurons [112, 120].…”