Protein Kinase C Signaling in Alzheimer's Disease Mechanisms

Protein kinase C (PKC) represents a family of serine/threonine kinases that regulate diverse cellular processes including synaptic plasticity, inflammatory responses and amyloid precursor protein (APP) processing. In Alzheimer’s disease (AD), dysregulated PKC signalling contributes to the accumulation of neurotoxic amyloid-β (Aβ) peptides, tau hyperphosphorylation and synaptic dysfunction. Certain PKC isoforms, notably PKCα, PKCδ and PKCε, modulate the balance between non-amyloidogenic α-secretase cleavage of APP and generation of Aβ, while also influencing microglial activation and proinflammatory pathways such as nuclear factor κB (NF-κB). Loss of PKCε activity in neuronal networks exacerbates Aβ accumulation by impairing the expression of clearance enzymes like neprilysin, whereas overactivity of PKCδ in microglia amplifies cytokine release and neuroinflammation. Furthermore, PKC-dependent phosphorylation of synaptic scaffolding proteins such as PSD-95 underlies synaptogenesis and maintenance of excitatory connectivity, processes that are compromised early in AD. The dual capacity of PKC to both protect and exacerbate neuronal injury underscores its isoform-specific roles as targets for therapeutic modulation.

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Protein Kinase C Signaling in Alzheimer's Disease Mechanisms publication trend

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Technical terms

Protein kinase C (PKC): A family of enzymes that phosphorylate serine/threonine residues in target proteins, regulating cellular signalling pathways.

Amyloid-β (Aβ): Peptide fragments derived from APP whose aggregation forms extracellular plaques, a hallmark of AD pathology.

α-Secretase: Enzyme that cleaves APP within the Aβ region, preventing formation of neurotoxic Aβ and producing neuroprotective soluble APP fragments.

Neuroinflammation: Inflammatory response within the central nervous system, often mediated by activated microglia and astrocytes, contributing to neuronal damage.

Neprilysin: Zinc-dependent endopeptidase that degrades Aβ peptides, facilitating their clearance from the brain.

Synaptogenesis: The formation and maturation of synaptic connections between neurons, essential for learning and memory.

References

1. PKCδ serves as a potential biomarker and therapeutic target for microglia‐mediated neuroinflammation in Alzheimer's disease. Alzheimer's & Dementia (2024).
2. Bryostatin-1: a promising compound for neurological disorders. Frontiers in Pharmacology (2023).
3. Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95*. Journal of Biological Chemistry (2016).
4. PKCε Promotes HuD-Mediated Neprilysin mRNA Stability and Enhances Neprilysin-Induced Aβ Degradation in Brain Neurons. PLOS ONE (2014).