PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling

Abstract

The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments. In the liver, LDLR is a major controller of blood LDL levels, whereas VLDLR and ApoER2 in the brain mediate Reelin signaling, a critical pathway for proper development of the nervous system. Expression level of PCSK9 in the brain is highest in the cerebellum during perinatal development, but is also increased in the adult brain after ischemia. The mechanism of PCSK9 function and its involvement in neuronal apoptosis is poorly understood. We show here that RNAimediated knockdown of PCSK9 significantly reduced the death of potassium-deprived cerebellar granule neurons (CGN), as shown by reduced levels of nuclear phosphorylated c-Jun and activated caspase-3, as well as condensed apoptotic nuclei. ApoER2 protein levels were increased in PCSK9 RNAi cells. Knockdown of ApoER2 but not of VLDLR was sufficient to reverse the protection provided by PCSK9 RNAi, suggesting that proapoptotic signaling of PCSK9 is mediated by altered ApoER2 function. Pharmacological inhibition of signaling pathways associated with lipoprotein receptors suggested that PCSK9 regulates neuronal apoptosis independently of NMDA receptor function but in concert with ERK and JNK signaling pathways. PCSK9 RNAi also reduced staurosporineinduced CGN apoptosis and axonal degeneration in the nerve growth factor-deprived dorsal root ganglion neurons. We conclude that PCSK9 potentiates neuronal apoptosis via modulation of ApoER2 levels and related anti-apoptotic signaling pathways.

Pcsk9

“…For example, in contrast to the LDLR, the GOF D374Y PCSK9 does not degrade these other receptors more efficiently than wild-type PCSK9. 42 The receptors LDLR, VLDLR, and ApoER2 have been confirmed as PCSK9 target proteins in mice 25,26,65,66 and the LDLR in monkeys 67 and human. 68 Recently, we showed that PCSK9 can enhance the degradation of LRP1 in various cells 44 although proof of this activity in vivo is still lacking.…”

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition

“…Like other members of the LDL-R family, VLDL-R and apoE receptor 2 undergo lysosomal degradation after binding of PCSK9 to the EGF-A domains of the receptors. 60,61 Notably, PCSK9 has been implicated in central nervous system development 62 and, as noted above, was shown to enhance neuronal apoptosis, 19,63 an effect mediated by degradation of the apoE receptor 2. 63 Conversely, inhibition of PCSK9 led to an increase in cell viability for up to 24 hours in the setting of neural apoptosis induced by potassium deprivation.…”

“…60,61 Notably, PCSK9 has been implicated in central nervous system development 62 and, as noted above, was shown to enhance neuronal apoptosis, 19,63 an effect mediated by degradation of the apoE receptor 2. 63 Conversely, inhibition of PCSK9 led to an increase in cell viability for up to 24 hours in the setting of neural apoptosis induced by potassium deprivation. 63 There is conflicting evidence bearing on the possibility of a relationship of brain PCSK9 expression to the pathophysiology of Alzheimer disease.…”

Potential of PCSK9 as a new target for the management of LDL cholesterol

“…In a recent animal study, the authors observed a proapoptotic effect in cerebellar neurons of PCSK9 (mediated by apoE receptor 2 degradation) that was independent of N-methyl-D-aspartate receptor function. 29 Some studies suggested involvement of this convertase in the development of Alzheimer's disease, 30,31 in that it is able to generate amyloid β-peptide. 32 Controversial findings came from other research.…”