Kinases regulating survival and APP processing

Kinases regulating survival and APP processing refers to a functional group of enzymes that play a pivotal role in the pathogenesis of Alzheimer's disease by modulating the metabolism of the amyloid precursor protein (APP) and influencing neuronal viability. This group includes key kinases such as glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CDK5), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), and protein kinase C (PKC). These enzymes regulate the phosphorylation of APP and the secretases involved in its cleavage, thereby shifting the balance between the neuroprotective non-amyloidogenic pathway and the neurotoxic amyloidogenic pathway that produces amyloid-beta (Aβ) plaques. Additionally, these kinases are central to signaling cascades that determine cell fate, often promoting apoptosis or neurodegeneration when dysregulated. Therapeutic strategies targeting these kinases aim to inhibit those that promote Aβ production and cell death (e.g., GSK-3β, CDK5) or activate those that favor neuroprotective APP processing (e.g., PKC). Despite their potential as therapeutic targets, drug development faces significant challenges, including the need for high brain penetrance and the risk of systemic toxicity due to the broad physiological roles of these kinases in other tissues.

Other names

APP-regulating kinasesSurvival-regulating kinasesGSK3/CDK5/DYRK1A/PKC group

Modulation of kinase activity to shift APP processing from the amyloidogenic to the non-amyloidogenic pathway and to enhance neuronal survival signaling.