Apolipoprotein ( APOA1,APOE,CLU ) genes expression in the CA3 region of the hippocampus in an ischemic model of Alzheimer's disease with survival up to 2 years
Restricted accessResearch articleFirst published online January, 2025
Apolipoprotein ( APOA1,APOE,CLU ) genes expression in the CA3 region of the hippocampus in an ischemic model of Alzheimer's disease with survival up to 2 years
Changes in the Alzheimer's disease-related apolipoprotein genes expression, occurring parallel with brain ischemia-induced neurodegeneration in the hippocampal CA3 area, may be crucial for the development of memory loss and dementia.
Objective
The aim of the study was to investigate changes in genes expression of apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and clusterin (CLU) in CA3 area post-ischemia with survival of 2 years.
Methods
The gene expression was evaluated with the use of an RT-PCR protocol after 2, 7, and 30 days and 6, 12, 18, and 24 months post-ischemia.
Results
The expression of the APOA1 gene (encoding apolipoprotein A1) was below the control values at 2 days, 6 and 12 months while at 7 and 30 days and 18 and 24 months post-ischemia this gene expression exceeded the control values. In the case of the CLU gene (encoding clusterin) expression, it was above the control values at all times post-ischemia. Similar expression was observed for the APOE gene (encoding apolipoprotein E) except on day 7 after ischemia where its expression was below the control value.
Conclusions
The results seem to indicate that the observed changes in the gene expression may reflect the activation and inhibition of a variety of processes involved in ischemia-induced neurodegeneration. The enhanced expression of APOA1 and CLU genes may be associated with induction of neuroprotective mechanisms while increased expression of the APOE gene may produce detrimental effects.
LanaDUgoliniFGiovanniniMG. An overview on the differential interplay among neurons-astrocytes-microglia in CA1 and CA3 hippocampus in hypoxia/ischemia. Front Cell Neurosci2020; 14: 585833.
2.
LiuHXZhangJJZhengP, et al.Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Mol Brain Res2005; 139: 169–177.
3.
BabcockKRPageJSFallonJR, et al.Adult hippocampal neurogenesis in aging and Alzheimer’s disease. Stem Cell Rep2021; 16: 681–693.
4.
TangYYanYMaoJ, et al.The hippocampus associated GABAergic neural network impairment in early-stage of Alzheimer’s disease. Ageing Res Rev2023; 86: 101865.
5.
PlutaRSalínskaEPukaM, et al.Early changes in extracellular amino acids and calcium concentrations in rabbit hippocampus following complete 15-min cerebral ischemia. Resuscitation1988; 16: 193–210.
6.
RossiDJOshimaTAttwellD. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature2000; 403: 316–321.
7.
PadurariuMCiobicaAMavroudisI, et al.Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer’s disease patients. Psychiatr Danub2012; 24: 152–158.
8.
PlutaRMiziakBCzuczwarSJ. Post-ischemic permeability of the blood-brain barrier to amyloid and platelets as a factor in the maturation of Alzheimer’s disease-type brain neurodegeneration. Int J Mol Sci2023; 24: 10739.
9.
RadenovicLNenadicMUłamek-KoziołM, et al.Heterogeneity in brain distribution of activated microglia and astrocytes in a rat ischemic model of Alzheimer’s disease after 2 years of survival. Aging2020; 12: 12251–12267.
10.
BeccariSSierra-TorreVValeroJ, et al.Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy. Autophagy2023; 19: 1952–1981.
11.
SweeneyMDSagareAPZlokovicBV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol2018; 14: 133–150.
12.
MuddapuVRDharshiniSAPChakravarthyVS, et al.Neurodegenerative diseases – is metabolic deficiency the root cause?Front Neurosci2020; 14: 213.
PlutaRCzuczwarSJ. Ischemia-reperfusion programming of Alzheimer’s disease-related genes – A new perspective on brain neurodegeneration after cardiac arrest. Int J Mol Sci2024; 25: 1291.
15.
PlutaRUłamek-KoziołMKockiJ, et al.Expression of the tau protein and amyloid protein precursor processing genes in the CA3 area of the hippocampus in the ischemic model of Alzheimer’s disease in the rat. Mol Neurobiol2020; 57: 1281–1290.
16.
CzuczwarSJKockiJMiziakB, et al.Alpha-, beta-, and gamma-secretase, amyloid precursor protein, and tau protein genes in the hippocampal CA3 subfield in an ischemic model of Alzheimer’s disease with survival up to 2 years. J Alzheimers Dis2024; 98: 151–161.
17.
Ułamek-KoziołMCzuczwarSJKockiJ, et al.Dysregulation of autophagy, mitophagy, and apoptosis genes in the CA3 region of the hippocampus in the ischemic model of Alzheimer’s disease in the rat. J Alzheimers Dis2019; 72: 1279–1286.
18.
PlutaRBogucka-KockaABoguckiJ, et al.Apoptosis, autophagy, and mitophagy genes in the CA3 area in an ischemic model of Alzheimer’s disease with 2-year survival. J Alzheimers Dis2024; 99: 1375–1383.
19.
PlutaRKockiJBoguckiJ, et al.LRP1 And RAGE genes transporting amyloid and tau protein in the hippocampal CA3 area in an ischemic model of Alzheimer’s disease with 2-year survival. Cells2023; 12: 2763.
20.
KidaEPlutaRLossinskyAS, et al.Complete cerebral ischemia with short-term survival in rat induced by cardiac arrest. II. Extracellular and intracellular accumulation of apolipoproteins E and J in the brain. Brain Res1995; 674: 341–346.
21.
Ułamek-KoziołMPlutaRBogucka-KockaA, et al.Brain ischemia with Alzheimer phenotype dysregulates Alzheimer’s disease-related proteins. Pharmacol Rep2016; 68: 582–591.
22.
PlutaR. The role of apolipoprotein E in the deposition of beta-amyloid peptide during ischemia-reperfusion brain injury. A model of early Alzheimer’s disease. Ann N Y Acad Sci2000; 903: 324–334.
23.
PlutaRBarcikowskaMDebickiG, et al.Changes in amyloid precursor protein and apolipoprotein E immunoreactivity following ischemic brain injury in rat with long-term survival: influence of idebenone treatment. Neurosci Lett1997; 232: 95–98.
24.
PlutaRLossinskyASMossakowskiMJ, et al.Reassessment of a new model of complete cerebral ischemia in rats. Method of induction of clinical death, pathophysiology and cerebrovascular pathology. Acta Neuropathol1991; 83: 1–11.
25.
ChomczynskiPSacchiN. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem1987; 162: 156–159.
26.
ButtonEBBoyceGKWilkinsonA, et al.ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice. Alzheimers Res Ther2019; 11: 44.
27.
Fernández-de RetanaSMontañolaAMarazuelaP, et al.Intravenous treatment with human recombinant ApoA-I Milano reduces beta amyloid cerebral deposition in the APP23-transgenic mouse model of Alzheimer’s disease. Neurobiol Aging2017; 60: 116–128.
28.
SoléMMarazuelaPCastelloteL, et al.Therapeutic effect of human ApoA-I-Milano variant in aged transgenic mouse model of Alzheimer’s disease. Br J Pharmacol2023; 180: 1999–2017.
29.
HallEDOostveenJADunnE, et al.Increased amyloid protein precursor and apolipoprotein E immunoreactivity in the selectively vulnerable hippocampus following transient forebrain ischemia in gerbils. Exp Neurol1995; 135: 17–27.
30.
IshimaruHIshikawaKOheY, et al.Cystatin C and apolipoprotein E immunoreactivities in CA1 neurons in ischemic gerbil hippocampus. Brain Res1996; 709: 155–162.
31.
KamadaHSatoKZhangWR, et al.Spatiotemporal changes of apolipoprotein E immunoreactivity and apolipoprotein E mRNA expression after transient middle cerebral artery occlusion in rat brain. J Neurosci Res2003; 73: 545–556.
32.
NishioMKohmuraEYuguchiT, et al.Neuronal apolipoprotein E is not synthesized in neuron after focal ischemia in rat brain. Neurol Res2003; 25: 390–394.
33.
AliSMDunnEOostveenJA, et al.Induction of apolipoprotein E mRNA in the hippocampus of the gerbil after transient global ischemia. Mol Brain Res1996; 38: 37–44.
34.
MahanTEWangCBaoX, et al.Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener2022; 17: 13.
35.
JabłońskiMMaciejewskiRJanuszewskiS, et al.One year follow up in ischemic brain injury and the role of Alzheimer factors. Physiol Res2011; 60(Suppl 1): S113–S119.
36.
HerringSKMoonH-JRawalP, et al.Brain clusterin protein isoforms and mitochondrial localization. Elife2019; 18: e48255.
37.
HumphreysDTCarverJAEasterbrook-SmithSB, et al.Clusterin has chaperone-like activity similar to that of small heat shock proteins. J Biol Chem1999; 274: 6875–6881.
38.
PoonSEasterbrook-SmithSBRybchynMS, et al.Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in folding-competent state. Biochemistry2000; 39: 15953–15960.
39.
WojtasAMKangSSOlleyBM, et al.Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A2017; 114: E6962–E6971.
40.
BellRDSagareAPFriedmanAE, et al.Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab2007; 27: 909–918.
41.
OdaTWalsPOsterburgHH, et al.Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress. Exp Neurol1995; 136: 22–31.
42.
PlutaRLossinskyASWiśniewskiHM, et al.Early blood-brain barrier changes in the rat following transient complete cerebral ischemia induced by cardiac arrest. Brain Res1994; 633: 41–52.
43.
PlutaRJanuszewskiSUłamekM. Ischemic blood-brain barrier and amyloid in white matter as etiological factors in leukoaraiosis. Acta Neurochir Suppl2008; 102: 353–356.
44.
SekeljicVBataveljicDStamenkovicS, et al.Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model. Brain Struct Funct2012; 217: 411–420.
45.
WigginsAKShenP-JGundlachAL. Delayed, but prolonged increases in astrocytic clusterin (ApoJ) mRNA expression following acute cortical spreading depression in the rat: evidence for a role of clusterin in ischemic tolerance. Mol Brain Res2003; 114: 20–30.
46.
ImhofACharnayYValletPG, et al.Sustained astrocytic clusterin expression improves remodeling after brain ischemia. Neurobiol Dis2006; 22: 274–283.
47.
LecordierSPonsVRivestS, et al.Multifocal cerebral microinfarcts modulate early Alzheimer’s disease pathology in a sex-dependent manner. Front Immunol2022; 12: 813536.
48.
PlutaR. A look at the etiology of Alzheimer’s disease based on the brain ischemia model. Curr Alzheimer Res2024; 21: 166–182.
49.
KirykAPlutaRFigielI, et al.Transient brain ischemia due to cardiac arrest causes irreversible long-lasting cognitive injury. Behav Brain Res2012; 219: 1–7.
50.
BabusikovaEDobrotaDTurnerAJ, et al.Effect of global brain ischemia on amyloid precursor protein metabolism and expression of amyloid-degrading enzymes in rat cortex: role in pathogenesis of Alzheimer’s disease. Biochemistry (Mosc)2021; 86: 680–692.
51.
WojtasAMSensJPKangSS, et al.Astrocyte-derived clusterin suppresses amyloid formation in vivo. Mol Neurodegener2020; 15: 71.
52.
SchreinerTGIgnatBEGrosuC, et al.Lipid-derived biomarkers as therapeutic targets for chronic coronary syndrome and ischemic stroke: an updated narrative review. Medicina (Kaunas)2024; 60: 56.
53.
XueYGuMChenC, et al.Apolipoprotein E mimetic peptide COG1410 alleviates blood-brain barrier injury in a rat model of ischemic stroke. Mol Med Rep2023; 27: 85.
