APOE and NF-κB in Alzheimer’s Disease: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Immunology
Contributor:
Don Davies

Apolipoprotein E (APOE) has three different isoforms, with APOE4 carriers representing a major risk factor for the development of Alzheimer’s disease (AD). The APOE4 isoform is associated with many pathological mechanisms, such as increased neuroinflammation. The presence of APOE4 can increase neuroinflammation via overactivation of the nuclear factor kappa B (NF-kB) pathway. The NF-kB pathway is a family of transcription factors involved with regulating over 400 genes involved with inflammation. AD is associated with sustained inflammation and an overactivation of the NF-kB pathway. Therefore, targeting the APOE4 isoform and suppressing the NF-kB pathway using anti-inflammatory compounds may result in the development of novel therapeutics for the prevention/treatment of AD.

  • neurodegeneration
  • neuroinflammation
  • APOE4
  • APOE3
  • APOE2

1. Introduction

Apolipoprotein E (APOE) has emerged as a therapeutic target for the treatment of AD. APOE is a cholesterol carrier that is involved with lipid transportation and repair in the brain [1]. APOE is a polymorphic protein with three isoforms, APOE4, APOE3, and APOE2, which differ from each other by two amino acid substitutions (arg/arg, cys/arg, and cys/cys, respectively), resulting in different tertiary structures and likely altering APOE function. 

2. APOE and Inflammation

APOE and its receptors play important roles in inflammatory responses that modulate the clearance of Aβ. APOE genotypes affect Aβ plaque deposition and can cause cerebral amyloid angiopathy (CAA) [2]. APOE is deposited in the plaques of patients with AD, and is more abundant in APOE4 carriers compared with non-APOE4 carriers [3][4][5][6]. PET scanning using Pittsburgh compound B (PiB) showed that fibrillar aggregates of Aβ were more common in people who are APOE4 carriers [7][8]. APOE4 carriers have high rates of fibrillar Aβ in frontal, posterior cingulate-precuneus, temporal, parietal, and basal ganglia regions of the brain [9]. Cognitively normal APOE4 carriers received PiB PET imaging that indicated fibrillar aggregates of Aβ at approximately 56 years of age, compared to approximately 76 years of age in non-APOE4 carriers [10]. These results have led to speculation that increases in fibrillar Aβ in APOE4 carriers in cognitively normal people may result in an increased risk of developing mild cognitive impairment (MCI) and/or AD in the future [11].
APOE has three different isoforms; however, mice express a single isoform, and it differs from the human APOE isoforms by approximately 100–300 amino acids [12]. The difference between human APOE and mouse APOE has led researchers to investigate the role of transcription factors in the expression of APOE, such as the LXRE consensus sequences in human and mouse APOE [13][14][15]. APOE knock-out mice were crossed with a transgenic mouse model of AD overexpressing a human mutant APP gene, resulting in PDAPP+/+; APOE −/− mice, which exhibited reduced Aβ deposits compared to PDAPP+/+; APOE +/+ mice [16]. PDAPP+/+; APOE −/− mice that expressed either human APOE2, APOE3, or APOE4 showed a reduction in Aβ40 in plasma as they aged for each isoform [17]. However, levels of Aβ40 and Aβ42 increased in the brain as the mice aged, regardless of the APOE isoform. Hippocampal insoluble Aβ40 and Aβ42 levels increased in an APOE isoform-dependent manner, with the highest levels in the APOE4 mice and the lowest levels in APOE2 mice.
The APOE4 mice had increased cytokine responses compared with APOE2 and APOE3 mice [18][19]. Cortical levels of IL-1β and the microglial reactivity in cortical plaques of APOE4 mice were increased compared to APOE3 mice [20]. Experimental autoimmune encephalomyelitis impaired learning and memory in APOE4 knock-in mice, suggesting that neuroinflammation affects learning and memory in APOE4 carriers [21]. Intravenous LPS administration increased pro-inflammatory cytokines, TNFα, and IL-6 in APOE4 mice compared to APOE3 mice [22]. Additionally, the administration of APOE mimetic peptide from the receptor-binding region decreased systemic and brain pro-inflammatory responses after administration with LPS. The APOE peptide was associated with the decreased activation of c-Jun N-terminal kinase (JNK) signaling [23]. The microglial lipoprotein receptors regulate JNK activity, and are necessary for APOE’s regulation of inflammation. The APOE mimetic peptide crosses the blood–brain barrier (BBB), and using peptides that can cross the BBB may be a novel therapeutic strategy for the treatment of AD [24].
APOE has anti-inflammatory effects in isolated macrophages via the APOE receptor-2, which result in macrophage conversion from pro-inflammatory M1 to the anti-inflammatory M2 [25]. Endogenous APOE from glial cell cultures inhibits microglial nitric oxide production [26]. The inhibition of inflammatory signaling increased APOE expression, which indicates that inflammation and APOE levels are involved in a negative feedback loop [27]. APOE deletion upregulates TLR4 and TLR2, and increases TLR activation [28][29]. The APOE protein is involved with an anti-inflammatory state, with APOE4 being the least anti-inflammatory, APOE2 being the most anti-inflammatory, and APOE3 being in the middle of the anti-inflammatory scale [30].

3. APOE and NF-κB

APOE is shown to modulate neuroinflammation via the NF-κB pathway. APOE4 mice showed increased NF-κB-regulated genes compared to APOE3 mice [31]. However, another study found that both APOE3 and APOE4 downregulated the NF-κB pathway [32]. These discrepant results may be due to the differences in methodology used between the two studies, with the in vivo experiment showing an increase in NF-κB activity and the in vitro experiment showing a decrease in NF- κB activity. APOE knock-out mice had increased inflammation and oxidative stress via activation of the NF-κB pathway [33]. PDAPP+/+; APOE −/− mice have reduced Aβ deposits in the cortex and hippocampus, and future studies should examine the NF-κB pathway in PDAPP+/+; APOE −/− mice [16]. Administration of the anti-inflammatory compounds Tanshinone IIA and Astragaloside IV in APOE knock-out mice suppressed the TLR4/NF-κB signaling pathway in vivo and in vitro [34]. Brain infusions of LPS in APOE4 mice were associated with the increased activation of the NF-κB pathway compared to APOE3 mice [35]. APOE4 mice showed increased nuclear translocation of NF-κB and increased IL-1β. The activation of the NF-κB pathway was increased after traumatic brain injury (TBI) in APOE4 mice compared to APOE3 mice [36]. APOE3 may inhibit the NF-κB pathway after TBI to alleviate BBB impairment. Schwann cells from APOE4 and APOE2 mice showed impaired cytokine production, which may have resulted from activation of the NF-κB pathway [37]. APOE activates the NF-κB pathway, inducing the expression of immunosuppressive chemokines Cxcl1 and Cxcl5 in tumor cells [38].
A high-fat diet and sedentary lifestyle can affect many medical conditions, including AD. APOE knock-out mice fed a high-fat diet had hypothalamic inflammation, glial cells activation, and cognition decline, which were reversed with diet control and exercise [39]. The diet control and exercise resulted in increased expressions of SIRT1 and the inhibition of the NF-κB pathway. Chronic stress is another important lifestyle factor that can influence various health conditions. Chronic unpredictable mild stress in APOE knock-out mice upregulated TLR4/NF-κB expression [40], and the administration of an NF-κB inhibitor downregulated the NF-κB pathway [41]. APOE knock-out mice that received AGEs via injection displayed increased Aβ formation and NF-κB p65 expression [42]. The statin medication atorvastatin decreased Aβ formation and suppressed AGEs-induced NF-κB p65 expression. PDAPP+/+; APOE −/− mice have decreased Aβ deposits, which contrasts with the previously mentioned experiment with increased Aβ formation. PDAPP+/+ mice are generated using a platelet-derived growth factor promoter with a human APP gene mutation associated with AD. Modafinil is prescribed for narcolepsy patients to increase wakefulness, and has anti-inflammatory effects. In APOE knock-out mice, modafinil inhibited the NF-κB pathway [43].
Vascular defects occurred in APOE4 mice before the neurodegenerative impairments occurred [44]. Astrocytes that secreted APOE3 and APOE2 but not APOE4 inhibited the cyclophilin A (CypA)-NF-κB–matrix-metalloproteinase-9 (MMP-9) pathway in pericytes, suggesting that APOE4 is a key target for the treatment of neurovascular conditions [45]. CypA has a variety of roles, including protein folding, trafficking and T cell activation, and is secreted from cells in response to inflammation [46]. MMP-9 is a type of enzyme in the zinc-metalloproteinases family involved with the breakdown of the extracellular matrix in both normal and pathological processes, including neurodegeneration [47]. The pro-inflammatory CypA–NF-κB–MMP-9 pathway causes BBB impairment via the MMP-9 degradation of tight junction proteins, which is associated with the onset of neurodegenerative disorders [44]. Additionally, astrocytes that secrete APOE3 and APOE2 have high binding affinities with lipoprotein receptor-related protein 1 (LRP1) [44]. However, astrocytes that secrete APOE4 have a low binding affinity with LRP1. In pericytes, the weak binding affinity of APOE4 to LRP1 leads to a reduction in Aβ clearance and a subsequent Aβ accumulation, resulting in neurodegeneration (see Figure 1). The inhibition of the CypA–NF-κB–MMP-9 pathway in APOE4 mice increased the coverage of tight junction proteins, prevented the loss of neurons and axon density, and improved cognitive function [48]. However, the inhibition of the CypA–NF-κB–MMP-9 pathway does not protect against Aβ accumulation.
Immuno 01 00027 g001 550
Figure 1. The proposed pathways involved with the interaction of apolipoprotein E (APOE) and nuclear factor kappa B (NF-κB). APOE4 protein secreted from astrocytes has a low binding affinity with the low-density lipoprotein receptor-related protein 1 (LRP1) and results in an increase in the cyclophilin A (CypA)–NF-κB–matrix metalloproteinase 9 (MMP-9) pathway (as represented by the red line). This also results in blood–brain barrier (BBB) damage via degradation of tight junctions.

This entry is adapted from the peer-reviewed paper 10.3390/immuno1040027

References

  1. Mahley, R.W.; Rall, S.C., Jr. Apolipoprotein E: Far more than a lipid transport protein. Annu. Rev. Genom. Hum. Genet. 2000, 1, 507–537.
  2. Ellis, R.J.; Olichney, J.M.; Thal, L.J.; Mirra, S.S.; Morris, J.C.; Beekly, D.; Heyman, A. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: The CERAD experience, Part XV. Neurology 1996, 46, 1592–1596.
  3. Namba, Y.; Tomonaga, M.; Kawasaki, H.; Otomo, E.; Ikeda, K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991, 541, 163–166.
  4. Kok, E.; Haikonen, S.; Luoto, T.; Huhtala, H.; Goebeler, S.; Haapasalo, H.; Karhunen, P.J. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann. Neurol. 2009, 65, 650–657.
  5. Polvikoski, T.; Sulkava, R.; Haltia, M.; Kainulainen, K.; Vuorio, A.; Verkkoniemi, A.; Niinisto, L.; Halonen, P.; Kontula, K. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N. Engl. J. Med. 1995, 333, 1242–1247.
  6. Schmechel, D.E.; Saunders, A.M.; Strittmatter, W.J.; Crain, B.J.; Hulette, C.M.; Joo, S.H.; Pericak-Vance, M.A.; Goldgaber, D.; Roses, A.D. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993, 90, 9649–9653.
  7. Klunk, W.E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D.P.; Bergstrom, M.; Savitcheva, I.; Huang, G.F.; Estrada, S.; et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann. Neurol. 2004, 55, 306–319.
  8. Barthel, H.; Gertz, H.J.; Dresel, S.; Peters, O.; Bartenstein, P.; Buerger, K.; Hiemeyer, F.; Wittemer-Rump, S.M.; Seibyl, J.; Reininger, C.; et al. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: A multicentre phase 2 diagnostic study. Lancet Neurol. 2011, 10, 424–435.
  9. Reiman, E.M.; Chen, K.; Liu, X.; Bandy, D.; Yu, M.; Lee, W.; Ayutyanont, N.; Keppler, J.; Reeder, S.A.; Langbaum, J.B.; et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2009, 106, 6820–6825.
  10. Fleisher, A.S.; Chen, K.; Liu, X.; Ayutyanont, N.; Roontiva, A.; Thiyyagura, P.; Protas, H.; Joshi, A.D.; Sabbagh, M.; Sadowsky, C.H.; et al. Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol. Aging 2013, 34, 1–12.
  11. Liu, C.C.; Liu, C.C.; Kanekiyo, T.; Xu, H.; Bu, G. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat. Rev. Neurol. 2013, 9, 106–118.
  12. Balu, D.; Karstens, A.J.; Loukenas, E.; Maldonado Weng, J.; York, J.M.; Valencia-Olvera, A.C.; LaDu, M.J. The role of APOE in transgenic mouse models of AD. Neurosci. Lett. 2019, 707, 134285.
  13. Chen, X.F.; Zhang, Y.W.; Xu, H.; Bu, G. Transcriptional regulation and its misregulation in Alzheimer’s disease. Mol. Brain 2013, 6, 44.
  14. Mandrekar-Colucci, S.; Landreth, G.E. Nuclear receptors as therapeutic targets for Alzheimer’s disease. Expert Opin. Ther. Targets 2011, 15, 1085–1097.
  15. Zannis, V.I.; Kan, H.Y.; Kritis, A.; Zanni, E.; Kardassis, D. Transcriptional regulation of the human apolipoprotein genes. Front. Biosci. 2001, 6, D456–D504.
  16. Bales, K.R.; Verina, T.; Dodel, R.C.; Du, Y.; Altstiel, L.; Bender, M.; Hyslop, P.; Johnstone, E.M.; Little, S.P.; Cummins, D.J.; et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 1997, 17, 263–264.
  17. Bales, K.R.; Liu, F.; Wu, S.; Lin, S.; Koger, D.; DeLong, C.; Hansen, J.C.; Sullivan, P.M.; Paul, S.M. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J. Neurosci. 2009, 29, 6771–6779.
  18. Rebeck, G.W. The role of APOE on lipid homeostasis and inflammation in normal brains. J. Lipid. Res. 2017, 58, 1493–1499.
  19. Zhu, Y.; Nwabuisi-Heath, E.; Dumanis, S.B.; Tai, L.M.; Yu, C.; Rebeck, G.W.; LaDu, M.J. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 2012, 60, 559–569.
  20. Rodriguez, G.A.; Tai, L.M.; LaDu, M.J.; Rebeck, G.W. Human APOE4 increases microglia reactivity at Abeta plaques in a mouse model of Abeta deposition. J. Neuroinflamm. 2014, 11, 111.
  21. Tu, J.L.; Zhao, C.B.; Vollmer, T.; Coons, S.; Lin, H.J.; Marsh, S.; Treiman, D.M.; Shi, J. APOE 4 polymorphism results in early cognitive deficits in an EAE model. Biochem. Biophys. Res. Commun. 2009, 384, 466–470.
  22. Lynch, J.R.; Tang, W.; Wang, H.; Vitek, M.P.; Bennett, E.R.; Sullivan, P.M.; Warner, D.S.; Laskowitz, D.T. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J. Biol. Chem. 2003, 278, 48529–48533.
  23. Pocivavsek, A.; Burns, M.P.; Rebeck, G.W. Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 2009, 57, 444–453.
  24. Lynch, J.R.; Wang, H.; Mace, B.; Leinenweber, S.; Warner, D.S.; Bennett, E.R.; Vitek, M.P.; McKenna, S.; Laskowitz, D.T. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury. Exp. Neurol. 2005, 192, 109–116.
  25. Baitsch, D.; Bock, H.H.; Engel, T.; Telgmann, R.; Muller-Tidow, C.; Varga, G.; Bot, M.; Herz, J.; Robenek, H.; von Eckardstein, A.; et al. Apolipoprotein E induces antiinflammatory phenotype in macrophages. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1160–1168.
  26. Laskowitz, D.T.; Matthew, W.D.; Bennett, E.R.; Schmechel, D.; Herbstreith, M.H.; Goel, S.; McMillian, M.K. Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide production. Neuroreport 1998, 9, 615–618.
  27. Pocivavsek, A.; Rebeck, G.W. Inhibition of c-Jun N-terminal kinase increases apoE expression in vitro and in vivo. Biochem. Biophys. Res. Commun. 2009, 387, 516–520.
  28. Goldklang, M.; Golovatch, P.; Zelonina, T.; Trischler, J.; Rabinowitz, D.; Lemaitre, V.; D’Armiento, J. Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in ApoE-deficient mice. Am. J. Physiol. Lung Cell Mol. Physiol. 2012, 302, L1200–L1208.
  29. Michelsen, K.S.; Doherty, T.M.; Shah, P.K.; Arditi, M. TLR signaling: An emerging bridge from innate immunity to atherogenesis. J. Immunol. 2004, 173, 5901–5907.
  30. Malik, M.; Parikh, I.; Vasquez, J.B.; Smith, C.; Tai, L.; Bu, G.; LaDu, M.J.; Fardo, D.W.; Rebeck, G.W.; Estus, S. Genetics ignite focus on microglial inflammation in Alzheimer’s disease. Mol. Neurodegener. 2015, 10, 52.
  31. Ophir, G.; Amariglio, N.; Jacob-Hirsch, J.; Elkon, R.; Rechavi, G.; Michaelson, D.M. Apolipoprotein E4 enhances brain inflammation by modulation of the NF-kappaB signaling cascade. Neurobiol. Dis. 2005, 20, 709–718.
  32. Noguchi, T.; Ebina, K.; Hirao, M.; Otsuru, S.; Guess, A.J.; Kawase, R.; Ohama, T.; Yamashita, S.; Etani, Y.; Okamura, G.; et al. Apolipoprotein E plays crucial roles in maintaining bone mass by promoting osteoblast differentiation via ERK1/2 pathway and by suppressing osteoclast differentiation via c-Fos, NFATc1, and NF-kappaB pathway. Biochem. Biophys. Res. Commun. 2018, 503, 644–650.
  33. Yang, X.; Chen, S.; Shao, Z.; Li, Y.; Wu, H.; Li, X.; Mao, L.; Zhou, Z.; Bai, L.; Mei, X.; et al. Apolipoprotein E deficiency exacerbates spinal cord injury in mice: Inflammatory response and oxidative stress mediated by NF-kappaB signaling pathway. Front. Cell Neurosci. 2018, 12, 142.
  34. Wang, N.; Zhang, X.; Ma, Z.; Niu, J.; Ma, S.; Wenjie, W.; Chen, J. Combination of tanshinone IIA and astragaloside IV attenuate atherosclerotic plaque vulnerability in ApoE(−/−) mice by activating PI3K/AKT signaling and suppressing TRL4/NF-kappaB signaling. Biomed. Pharmacother. 2020, 123, 109729.
  35. Ophir, G.; Mizrahi, L.; Michaelson, D.M. Enhanced activation of NF-kB signaling by apolipoprotein E4. In Advances in Alzheimer’s and Parkinson’s Disease; Springer: Boston, MA, USA, 2008.
  36. Teng, Z.; Guo, Z.; Zhong, J.; Cheng, C.; Huang, Z.; Wu, Y.; Tang, S.; Luo, C.; Peng, X.; Wu, H.; et al. ApoE influences the blood-brain barrier through the NF-kappaB/MMP-9 pathway after traumatic brain injury. Sci. Rep. 2017, 7, 6649.
  37. Zhang, K.J.; Zhang, H.L.; Zhang, X.M.; Zheng, X.Y.; Quezada, H.C.; Zhang, D.; Zhu, J. Apolipoprotein E isoform-specific effects on cytokine and nitric oxide production from mouse Schwann cells after inflammatory stimulation. Neurosci. Lett. 2011, 499, 175–180.
  38. Kemp, S.B.; Carpenter, E.S.; Steele, N.G.; Donahue, K.L.; Nwosu, Z.C.; Pacheco, A.; Velez-Delgado, A.; Menjivar, R.E.; Lima, F.; The, S.; et al. Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-kappaB-mediated production of CXCL1. Cancer Res. 2021, 81, 4305–4318.
  39. Wang, X.; Yang, J.; Lu, T.; Zhan, Z.; Wei, W.; Lyu, X.; Jiang, Y.; Xue, X. The effect of swimming exercise and diet on the hypothalamic inflammation of ApoE−/− mice based on SIRT1-NF-kappaB-GnRH expression. Aging 2020, 12, 11085–11099.
  40. Gu, H.; Tang, C.; Peng, K.; Sun, H.; Yang, Y. Effects of chronic mild stress on the development of atherosclerosis and expression of toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice. J. Biomed. Biotechnol. 2009, 2009, 613879.
  41. Tang, Y.L.; Jiang, J.H.; Wang, S.; Liu, Z.; Tang, X.Q.; Peng, J.; Yang, Y.Z.; Gu, H.F. TLR4/NF-kappaB signaling contributes to chronic unpredictable mild stress-induced atherosclerosis in ApoE−/− mice. PLoS ONE 2015, 10, e0123685.
  42. Li, Z.; Yang, P.; Feng, B. Effect of atorvastatin on AGEs-induced injury of cerebral cortex via inhibiting NADPH oxidase -NF-kappaB pathway in ApoE(−/−) mice. Mol. Biol. Rep. 2020, 47, 9479–9488.
  43. Han, J.; Chen, D.; Liu, D.; Zhu, Y. Modafinil attenuates inflammation via inhibiting Akt/NF-kappaB pathway in apoE-deficient mouse model of atherosclerosis. Inflammopharmacology 2018, 26, 385–393.
  44. Zlokovic, B.V. Cerebrovascular effects of apolipoprotein E: Implications for Alzheimer disease. JAMA Neurol. 2013, 70, 440–444.
  45. Bell, R.D.; Winkler, E.A.; Singh, I.; Sagare, A.P.; Deane, R.; Wu, Z.; Holtzman, D.M.; Betsholtz, C.; Armulik, A.; Sallstrom, J.; et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 2012, 485, 512–516.
  46. Nigro, P.; Pompilio, G.; Capogrossi, M.C. Cyclophilin A: A key player for human disease. Cell Death Dis. 2013, 4, e888.
  47. Kaplan, A.; Spiller, K.J.; Towne, C.; Kanning, K.C.; Choe, G.T.; Geber, A.; Akay, T.; Aebischer, P.; Henderson, C.E. Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron 2014, 81, 333–348.
  48. Montagne, A.; Nikolakopoulou, A.M.; Huuskonen, M.T.; Sagare, A.P.; Lawson, E.J.; Lazic, D.; Rege, S.; Grond, A.; Zuniga, E.; Zlokovic, B.V.; et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nat. Aging 2021, 1, 506–520.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback