Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by decreased glucose metabolism and increased neuroinflammation. Hexokinase (HK) is the key enzyme of glucose metabolism and is associated with mitochondria to exert its function. Recent studies have demonstrated that the dissociation of HK from mitochondria is enough to activate the NOD-like receptor protein 3 (NLRP3) inflammasome and leads to the release of interleukin-1β (IL-1β). However, the effect of increased IL-1β on the expression of HK is still unclear in AD. In this paper, we used positron emission tomography (PET), Western blotting and immunofluorescence to study the glucose metabolism, and the expression and distribution of HK in AD. Furthermore, we used lipopolysaccharide (LPS), nigericin (Nig), CY-09 and lonidamine (LND) to treat N2a and N2a-sw cells to investigate the link between IL-1β and HK in AD. The results show decreased expression of HK and the dissociation of HK from mitochondria in AD. Furthermore, a reduction of the expression of IL-1β could increase the expression of HK in AD. These results suggest that inhibiting inflammation may help to restore glucose metabolism in AD.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by decreased glucose metabolism and increased neuroinflammation [1,2]
It has been found in several studies that decreased glucose metabolism is associated with the low expression and activity of hexokinase (HK) [3,4], which is the key enzyme in glycolysis
It promotes the release of mitochondrial reactive oxygen species (ROS) and the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome
Summary
Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by decreased glucose metabolism and increased neuroinflammation [1,2]. The dissociation of HK from mitochondria leads to the disruption of the NAD+/NADH ratio, depolarization of membrane potential, and opening of the mitochondrial permeability transition pore It promotes the release of mitochondrial ROS and the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. It causes the release of pro-apoptotic factors and subsequent apoptosis [8,9,10,11,12]. NLRP3 contains a pyrin domain, a nucleotide-binding site domain and a leucine-rich repeat motif It interacts with the apoptosis-associated specklike protein ASC and recruits pro-caspase-1 to form the NLRP3 inflammasome complex. G18Fu-FpDtaGkuepintakneoinn-ntroann-tsrganesngiecn(iNc (TNgT)ga) nanddttrriippllee--ttrraannsgsegneinc i(c3 (×3 T×gT) gA)lzAhlezimheerim’s edris’esadseis(eAaDse) m(AicDe.)(am) sicheo.w(sa) shows coronal,csoarognitatla, slaagnitdtatlraanndstvreanrsseveirmseaigmeasg, easn, dan(db()bp) rperseesennttsstthhee ssttaannddaardrdiziezdeudputapkteavkaeluveaslu(SeUsV(Ss)UinVtsh)eiwn htholeewbrhaionl,ecborrtaeixn, cortex and hipapnodcahmipppoucsaminpNusTing NanTdg a3n×d T3 g×ATgDAmDicmei.c(en. (=n 6=,6m, meaeann±±SSDD,,SSttuuddeenntt’’sst-tt-etsets,t*, p*
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