Fig. 2.
Interplay between REST and miR-132/miR-124 (direct interaction, indirect interaction) and miR-124-APOE interplay in Aβ clearance: plausible involvement of microglia. a REST deficiency, direct REST-mediated miR-132, 9 dysregulation, and concurrent miR target deficits in AD (REST loss and concomitant miR-124 upregulation induce AD). In Aβ1-42 oligomer (green) treated cells, a decrease in REST occurs and reduced nuclear REST translocation is brought on by the switch of APOE3 to APOE4 expression (blue). In the end, REST failure leads to an increase in miR-124 and a decrease in PTPN1, which in turn encourages tau activation. miR-132 elevation was also shown to be a mediator of Sirtuin 1 (SIRT1) suppression after REST loss, which has an impact on longevity and aging. b REST and miR-124/miR-132 both individually influence the CDK5/calpain pathway in AD (REST loss induces AD, miR-124 prevents AD). Aβ1-42 induced CDK5R1 overexpression brought on by REST loss was shown. REST loss results in p35/CDK5R1 upregulation, which in turn results in calpain mediated CDK5/p25 activation. Hyperactivated results in BACE-1 phosphorylation and enhanced BACE-1 activity. On the other hand, BACE1-AS stabilizes BACE-1 and initializes BACE-1 genesis. miR-132-3p is inhibited by BACE1 antisense RNA (BACE1-AS). By blocking calpain in a route unrelated to REST action, miR-124 upregulation prevents Aβ1-42 driven CDK5R1 overexpression brought on by REST loss and contemporaneous CDK5 activation. miR-124 entry into the brain by DNA nanoflowers mediated miR-124 entry into the brain also suppresses BACE-1 activity and inhibits Aβ genesis. c The miR-124-APOE interplay in Aβ clearance: plausible involvement of microglia. Following a mild exposure to hydrogen peroxide, BV2 cells showed a decrease in miR-124 and APOE expression as well as an increase in RFX1 protein level. RFX1 inhibits APOE and impairs Aβ clearance. Microglial exosomes with a prominent elevation of miR-124-3p (Exo-124) result in decreased RELA, which in turn prevents APOE inhibition by RELA and proteolytic breakdown of the amyloid protein in damaged hippocampus neurons. Abbreviations: Aβ, amyloid beta; H2O2, hydrogen peroxide; APOE, apolipoprotein; CDK5, cyclin-dependent kinase 5; CDK5R1, cyclin-dependent kinase 5 activators 1 (P35); PTPN1, tyrosine-protein phosphatase nonreceptor type 1; Exo-124, microglial exosomes have more miR124-3p; SIRT1, Sirtuin 1; RELA, v-rel avian reticuloendotheliosis; BACE1-AS, BACE1 antisense RNA