The Interplay between PKC and ELAV4 in the CNS: An Emerging Therapeutic Axis for Dementia Management

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for 60-80% of all cases and characterized by amyloid beta (Aβ) plaques and tau protein hyperphosphorylation. Among the signaling mechanisms implicated in AD, protein kinase C (PKC) isoforms and neuron-specific embryonic lethal abnormal vision-4 (ELAV4) have gained increasing attention due to their roles in synaptic plasticity, neuroinflammation, and mRNA stability. This review discusses the potential for targeting the PKC-ELAV4 axis to manage dementia. PKC isoforms, including PKC α, δ, and ε, are involved in amyloid-beta (Aβ) processing, tau phosphorylation, and regulation of mitochondrial activities, whereas ELAV4 stabilizes mRNAs that participate in both the degradation of Aβ (e.g., neprilysin) and the synthesis of Aβ (e.g., beta-site amyloid precursor protein cleaving enzyme 1, BACE1). We reviewed 75 papers published over the last 15 years using search terms such as neuroinflammation, synaptic plasticity, mRNA stability in dementia, ELAV, ELAV4, PKC, and PKC isoforms in databases including PubMed, WOS, and Google Scholar. Results were summarized, compared, and research gaps were identified during data collection and interpretation. ELAV4 can influence the processing of amyloid precursor protein (APP), the precursor of the amyloid-beta peptide, a hallmark of AD. Decreased expression of ELAV4 in the hippocampus is associated with dementia. PKC-δ activates c-Jun N-terminal kinase (JNK) expression, releases Beclin-1 from the Bcl2/Beclin-1 complex, and promotes autophagy. Oxidative stress and PKC η regulate the mitogenactivated protein kinase (MAPK) pathway, leading to tau phosphorylation and neuronal death. PKCε activators and ELAV4 inhibitors have positive effects on cognitive function and dementia management by inhibiting neuroinflammation and neuronal apoptosis, while PKC α, β, δ inhibitors may aid in managing different forms of dementia. This review highlights research gaps and proposes future directions for targeting the PKC-ELAV4 axis as a novel strategy in dementia management.