The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis
Abstract
:1. Introduction
2. Neuroinflammation in AD
3. Brain Iron and Aging
4. Regulation of Iron Homeostasis
5. Butyrylcholinesterase in AD
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Scheltens, P.; Blennow, K.; Breteler, M.M.B.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; Van der Flier, W.M. Alzheimer’s disease. Lancet 2016, 388, 505–517. [Google Scholar] [CrossRef]
- Gold, C.A.; Budson, A.E. Memory loss in Alzheimer’s disease: Implications for development of therapeutics. Expert Rev. Neurother. 2008, 8, 1879–1891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davies, P. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 1976, 308, 1403. [Google Scholar] [CrossRef]
- Ball, M.J. Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. Acta Neuropathol. 1977, 37, 111–118. [Google Scholar] [CrossRef]
- Serrano-Pozo, A.; Frosch, M.P.; Masliah, E.; Hyman, B.T. Neuropathological Alterations in Alzheimer Disease. Cold Spring Harb. Perspect. Med. 2011, 1, 1–23. [Google Scholar] [CrossRef] [PubMed]
- West, M.; Coleman, P.; Flood, D.; Troncoso, J. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 1994, 344, 769–772. [Google Scholar] [CrossRef]
- Lane, R.M.; Potkin, S.G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol. 2005, 9, 101–124. [Google Scholar] [CrossRef]
- Szeto, J.Y.Y.; Lewis, S.J.G. Current Treatment Options for Alzheimer’s Disease and Parkinson’s Disease Dementia. Curr. Neuropharmacol. 2016, 14, 326–338. [Google Scholar] [CrossRef]
- Grutzendler, J.; Morris, J.C. Cholinesterase Inhibitors for Alzheimer’s disease. Drugs 2001, 61, 41–52. [Google Scholar] [CrossRef]
- Haam, J.; Yakel, J.L. Cholinergic modulation of the hippocampal region and memory function. J. Neurochem. 2017, 142, 111–121. [Google Scholar] [CrossRef] [Green Version]
- Lee, J.-H.; Jeong, S.-K.; Kim, B.C.; Park, K.W.; Dash, A. Donepezil across the spectrum of Alzheimer’s disease: Dose optimization and clinical relevance. Acta Neurol. Scand. 2015, 131, 259–267. [Google Scholar] [CrossRef] [PubMed]
- Bergmann, K.; Tomlinson, B.E.; Blessed, G.; Gibson, P.H.; Perry, R.H. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br. Med. J. 1978, 2, 1457–1459. [Google Scholar]
- Hyman, B.T.; Trojanowski, J.Q. Editorial on Consensus Recommendations for the Postmortem Diagnosis of Alzheimer Disease from the National Institute on Aging and the Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer Disease. J. Neuropathol. Exp. Neurol. 1997, 56, 1095–1097. [Google Scholar] [CrossRef] [Green Version]
- Whitehouse, P.J.; Price, D.L.; Struble, R.G.; Clark, A.W.; Coyle, J.T.; DeLong, M.R. Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science 1982, 215, 1237–1239. [Google Scholar] [CrossRef]
- Ballatore, C.; Lee, V.M.Y.; Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 2007, 8, 663–672. [Google Scholar] [CrossRef] [PubMed]
- Hebert, L.E. Age-Specific Incidence of Alzheimer’s Disease in a Community Population. JAMA J. Am. Med. Assoc. 1995, 273, 1354–1359. [Google Scholar] [CrossRef]
- Buxbaum, J.N. Alzheimer’s Disease: It’s More Than Aβ. FASEB J. 2017, 31, 2–4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jun, G. Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions with APOE Genotypes. Arch. Neurol. 2010, 67, 1473–1484. [Google Scholar] [CrossRef]
- Lambert, J.-C.; Heath, S.; Even, G.; Campion, D.; Sleegers, K.; Hiltunen, M.; Combarros, O.; Zelenika, D.; Bullido, M.J.; Tavernier, B.; et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 2009, 41, 1094–1099. [Google Scholar] [CrossRef]
- Corder, E.; Saunders, A.; Strittmatter, W.; Schmechel, D.; Gaskell, P.; Small, G.; Roses, A.; Haines, J.; Pericak-Vance, M. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993, 261, 921–923. [Google Scholar] [CrossRef]
- Seshadri, S. Genome-wide Analysis of Genetic Loci Associated with Alzheimer Disease. JAMA 2010, 303, 1832–1840. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lucotte, G.; Visvikis, S.; Leininger-Möler, B.; David, F.; Berriche, S.; Revéilleau, S.; Couderc, R.; Babron, M.C.; Aguillon, D.; Siest, G. Association of apolipoprotein E allele ε4 with late-onset sporadic Alzheimer’s disease. Am. J. Med. Genet. 1994, 54, 286–288. [Google Scholar] [CrossRef]
- 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, 52–64. [Google Scholar] [CrossRef] [Green Version]
- Gratuze, M.; Leyns, C.E.G.; Holtzman, D.M. New insights into the role of TREM2 in Alzheimer’s disease. Mol. Neurodegener. 2018, 13, 66–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Christie, R.H.; Bacskai, B.J.; Zipfel, W.R.; Williams, R.M.; Kajdasz, S.T.; Webb, W.W.; Hyman, B.T. Growth Arrest of Individual Senile Plaques in a Model of Alzheimer’s Disease Observed by In Vivo Multiphoton Microscopy. J. Neurosci. 2001, 21, 858–864. [Google Scholar] [CrossRef] [Green Version]
- Yeh, F.L.; Wang, Y.; Tom, I.; Gonzalez, L.C.; Sheng, M. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron 2016, 91, 328–340. [Google Scholar] [CrossRef] [PubMed]
- DeMattos, R.B.; Cirrito, J.R.; Parsadanian, M.; May, P.C.; O’Dell, M.A.; Taylor, J.W.; Harmony, J.A.K.; Aronow, B.J.; Bales, K.R.; Paul, S.M.; et al. ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition: Evidence that ApoE Regulates Extracellular Aβ Metabolism In Vivo. Neuron 2004, 41, 193–202. [Google Scholar] [CrossRef] [Green Version]
- Foster, E.M.; Dangla-Valls, A.; Lovestone, S.; Ribe, E.M.; Buckley, N.J. Clusterin in Alzheimer’s disease: Mechanisms, genetics, and lessons from other pathologies. Front. Neurosci. 2019, 13, 1–27. [Google Scholar] [CrossRef] [Green Version]
- Yamazaki, Y.; Zhao, N.; Caulfield, T.R.; Liu, C.-C.; Bu, G. Apolipoprotein E and Alzheimer disease: Pathobiology and targeting strategies. Nat. Rev. Neurol. 2019, 15, 501–518. [Google Scholar] [CrossRef]
- Kumar, R.; Nordberg, A.; Darreh-Shori, T. Amyloid-β peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAβACs. Brain 2016, 139, 174–192. [Google Scholar] [CrossRef] [Green Version]
- Zhao, J.; Davis, M.D.; Martens, Y.A.; Shinohara, M.; Graff-Radford, N.R.; Younkin, S.G.; Wszolek, Z.K.; Kanekiyo, T.; Bu, G. APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum. Mol. Genet. 2017, 26, 2690–2700. [Google Scholar] [CrossRef]
- Ulrich, J.D.; Ulland, T.K.; Mahan, T.E.; Nyström, S.; Nilsson, K.P.; Song, W.M.; Zhou, Y.; Reinartz, M.; Choi, S.; Jiang, H.; et al. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 2018, 215, 1047–1058. [Google Scholar] [CrossRef] [PubMed]
- Fernandez, C.G.; Hamby, M.E.; McReynolds, M.L.; Ray, W.J. The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease. Front. Aging Neurosci. 2019, 11, 14–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, T.; Chen, D.; Lee, T.H. Phosphorylation Signaling in APP Processing in Alzheimer’s Disease. Int. J. Mol. Sci. 2019, 21, 209. [Google Scholar] [CrossRef] [Green Version]
- Zhou, R.; Yang, G.; Guo, X.; Zhou, Q.; Lei, J.; Shi, Y. Recognition of the amyloid precursor protein by human γ-secretase. Science 2019, 363, eaaw0930. [Google Scholar] [CrossRef] [PubMed]
- Chen, G.; Xu, T.; Yan, Y.; Zhou, Y.; Jiang, Y.; Melcher, K.; Xu, H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017, 38, 1205–1235. [Google Scholar] [CrossRef]
- Demuro, A.; Mina, E.; Kayed, R.; Milton, S.C.; Parker, I.; Glabe, C.G. Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers. J. Biol. Chem. 2005, 280, 17294–17300. [Google Scholar] [CrossRef] [Green Version]
- Prangkio, P.; Yusko, E.C.; Sept, D.; Yang, J.; Mayer, M. Multivariate Analyses of Amyloid-Beta Oligomer Populations Indicate a Connection between Pore Formation and Cytotoxicity. PLoS ONE 2012, 7, e47261. [Google Scholar] [CrossRef]
- Pedersen, W.A.; Kloczewiak, M.A.; Blusztajn, J.K. Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain. Proc. Natl. Acad. Sci. USA 1996, 93, 8068–8071. [Google Scholar] [CrossRef] [Green Version]
- Smith, M.A.; Zhu, X.; Tabaton, M.; Liu, G.; McKeel, D.W.; Cohen, M.L.; Wang, X.; Siedlak, S.L.; Dwyer, B.E.; Hayashi, T.; et al. Increased Iron and Free Radical Generation in Preclinical Alzheimer Disease and Mild Cognitive Impairment. J. Alzheimer’s Dis. 2010, 19, 363–372. [Google Scholar] [CrossRef] [Green Version]
- Maynard, C.J.; Cappai, R.; Volitakis, I.; Cherny, R.A.; White, A.R.; Beyreuther, K.; Masters, C.L.; Bush, A.I.; Li, Q.-X. Overexpression of Alzheimer’s Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron. J. Biol. Chem. 2002, 277, 44670–44676. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Archer, H.A.; Edison, P.; Brooks, D.J.; Barnes, J.; Frost, C.; Yeatman, T.; Fox, N.C.; Rossor, M.N. Amyloid load and cerebral atrophy in Alzheimer’s disease: An 11 C-PIB positron emission tomography study. Ann. Neurol. 2006, 60, 145–147. [Google Scholar] [CrossRef]
- Klunk, W.E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D.P.; Bergström, 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. [Google Scholar] [CrossRef]
- Bennett, D.A.; Schneider, J.A.; Arvanitakis, Z.; Kelly, J.F.; Aggarwal, N.T.; Shah, R.C.; Wilson, R.S. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006, 66, 1837–1844. [Google Scholar] [CrossRef] [PubMed]
- Aizenstein, H.J.; Nebes, R.D.; Saxton, J.A.; Price, J.C.; Mathis, C.A.; Tsopelas, N.D.; Ziolko, S.K.; James, J.A.; Snitz, B.E.; Houck, P.R.; et al. Frequent Amyloid Deposition without Significant Cognitive Impairment Among the Elderly. Arch. Neurol. 2008, 65, 1509–1517. [Google Scholar] [CrossRef] [PubMed]
- Drachman, D.A. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimer’s Dement. 2014, 10, 372–380. [Google Scholar] [CrossRef]
- Jansen, W.J.; Ossenkoppele, R.; Knol, D.L.; Tijms, B.M.; Scheltens, P.; Verhey, F.R.J.; Visser, P.J.; Aalten, P.; Aarsland, D.; Alcolea, D.; et al. Prevalence of Cerebral Amyloid Pathology in Persons without Dementia. JAMA 2015, 313, 1924–1938. [Google Scholar] [CrossRef] [PubMed]
- Ayton, S.; Wang, Y.; Diouf, I.; Schneider, J.A.; Brockman, J.; Morris, M.C.; Bush, A.I. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol. Psychiatry 2020, 25, 2932–2941. [Google Scholar] [CrossRef]
- Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017, 171, 273–285. [Google Scholar] [CrossRef] [Green Version]
- Zecca, L.; Gallorini, M.; Schünemann, V.; Trautwein, A.X.; Gerlach, M.; Riederer, P.; Vezzoni, P.; Tampellini, D. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: Consequences for iron storage and neurodegenerative processes. J. Neurochem. 2001, 76, 1766–1773. [Google Scholar] [CrossRef]
- Trinder, D.; Fox, C.; Vautier, G.; Olynyk, J.K. Molecular pathogenesis of iron overload. Gut 2002, 51, 290–295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hentze, M.W.; Muckenthaler, M.U.; Galy, B.; Camaschella, C. Two to Tango: Regulation of Mammalian Iron Metabolism. Cell 2010, 142, 24–38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nnah, I.; Wessling-Resnick, M. Brain Iron Homeostasis: A Focus on Microglial Iron. Pharmaceuticals 2018, 11, 129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kruszewski, M. Labile iron pool: The main determinant of cellular response to oxidative stress. Mutat. Res. Fundam. Mol. Mech. Mutagenes. 2003, 531, 81–92. [Google Scholar] [CrossRef]
- Halliwell, B. Oxidative stress and neurodegeneration: Where are we now? J. Neurochem. 2006, 97, 1634–1658. [Google Scholar] [CrossRef] [PubMed]
- Crichton, R. Iron Metabolism; John Wiley & Sons, Ltd.: Chichester, UK, 2016; ISBN 9781118925645. [Google Scholar]
- Beard, J.L.; Connor, J.R. Iron status and neural functioning. Annu. Rev. Nutr. 2003, 23, 41–58. [Google Scholar] [CrossRef] [PubMed]
- Dixon, S.J. Ferroptosis: Bug or feature? Immunol. Rev. 2017, 277, 150–157. [Google Scholar] [CrossRef] [PubMed]
- Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015, 14, 388–405. [Google Scholar] [CrossRef] [Green Version]
- Steele, T.M.; Frazer, D.M.; Anderson, G.J. Systemic regulation of intestinal iron absorption. IUBMB Life 2005, 57, 499–503. [Google Scholar] [CrossRef] [PubMed]
- Qian, Z.; Ke, Y. Brain iron transport. Biol. Rev. 2019, 94, 1672–1684. [Google Scholar] [CrossRef]
- Duck, K.A.; Simpson, I.A.; Connor, J.R. Regulatory mechanisms for iron transport across the blood-brain barrier. Biochem. Biophys. Res. Commun. 2017, 494, 70–75. [Google Scholar] [CrossRef] [PubMed]
- Yanatori, I.; Kishi, F. Free Radical Biology and Medicine DMT1 and iron transport. Free Radic. Biol. Med. 2019, 133, 55–63. [Google Scholar] [CrossRef]
- Nemeth, E. Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science 2004, 306, 2090–2093. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, W.; Knovich, M.A.; Coffman, L.G.; Torti, F.M.; Torti, S.V. Serum ferritin: Past, present and future. Biochim. Biophys. Acta Gen. Subj. 2010, 1800, 760–769. [Google Scholar] [CrossRef] [Green Version]
- Arosio, P.; Elia, L.; Poli, M. Ferritin, cellular iron storage and regulation. IUBMB Life 2017, 69, 414–422. [Google Scholar] [CrossRef] [PubMed]
- Watt, R.K. A Unified Model for Ferritin Iron Loading by the Catalytic Center: Implications for Controlling “Free Iron” during Oxidative Stress. ChemBioChem 2013, 14, 415–419. [Google Scholar] [CrossRef]
- Moos, T.; Morgan, E.H. Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. J. Neurosci. Res. 1998, 54, 486–494. [Google Scholar] [CrossRef]
- Moos, T.; Nielsen, T.R.; Skjørringe, T.; Morgan, E.H. Iron trafficking inside the brain. J. Neurochem. 2007, 103, 1730–1740. [Google Scholar] [CrossRef]
- Codazzi, F.; Pelizzoni, I.; Zacchetti, D.; Grohovaz, F. Iron entry in neurons and astrocytes: A link with synaptic activity. Front. Mol. Neurosci. 2015, 8, 18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Connor, J.R.; Menzies, S.L. Cellular management of iron in the brain. J. Neurol. Sci. 1995, 134, 33–44. [Google Scholar] [CrossRef]
- Todorich, B.; Zhang, X.; Connor, J.R. H-ferritin is the major source of iron for oligodendrocytes. Glia 2011, 59, 927–935. [Google Scholar] [CrossRef]
- Chen, T.T.; Li, L.; Chung, D.H.; Allen, C.D.C.; Torti, S.V.; Torti, F.M.; Cyster, J.G.; Chen, C.Y.; Brodsky, F.M.; Niemi, E.C.; et al. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J. Exp. Med. 2005, 202, 955–965. [Google Scholar] [CrossRef] [PubMed]
- Chiou, B.; Lucassen, E.; Sather, M.; Kallianpur, A.; Connor, J. Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuro-immune axis. Glia 2018, 66, 1317–1330. [Google Scholar] [CrossRef]
- Abreu, R.; Quinn, F.; Giri, P.K. Role of the hepcidin-ferroportin axis in pathogen-mediated intracellular iron sequestration in human phagocytic cells. Blood Adv. 2018, 2, 1089–1100. [Google Scholar] [CrossRef]
- Nemeth, E.; Valore, E.V.; Territo, M.; Schiller, G.; Lichtenstein, A.; Ganz, T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003, 101, 2461–2463. [Google Scholar] [CrossRef] [PubMed]
- Nemeth, E.; Rivera, S.; Gabayan, V.; Keller, C.; Taudorf, S.; Pedersen, B.K.; Ganz, T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Investig. 2004, 113, 1271–1276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vela, D. Hepcidin, an emerging and important player in brain iron homeostasis. J. Transl. Med. 2018, 16, 1–18. [Google Scholar] [CrossRef] [Green Version]
- Qian, Z.-M.; He, X.; Liang, T.; Wu, K.-C.; Yan, Y.-C.; Lu, L.-N.; Yang, G.; Luo, Q.Q.; Yung, W.-H.; Ke, Y. Lipopolysaccharides Upregulate Hepcidin in Neuron via Microglia and the IL-6/STAT3 Signaling Pathway. Mol. Neurobiol. 2014, 50, 811–820. [Google Scholar] [CrossRef]
- Colonna, M.; Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 2017, 35, 441–468. [Google Scholar] [CrossRef] [PubMed]
- Chhabra, R.; Saha, A.; Chamani, A.; Schneider, N.; Shah, R.; Nanjundan, M. Iron Pathways and Iron Chelation Approaches in Viral, Microbial, and Fungal Infections. Pharmaceuticals 2020, 13, 275. [Google Scholar] [CrossRef] [PubMed]
- Coffey, R.; Ganz, T. Iron homeostasis: An anthropocentric perspective. J. Biol. Chem. 2017, 292, 12727–12734. [Google Scholar] [CrossRef] [Green Version]
- Reed-Geaghan, E.G.; Savage, J.C.; Hise, A.G.; Landreth, G.E. CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation. J. Neurosci. 2009, 29, 11982–11992. [Google Scholar] [CrossRef]
- Sfera, A.; Gradini, R.; Cummings, M.; Diaz, E.; Price, A.I.; Osorio, C. Rusty Microglia: Trainers of Innate Immunity in Alzheimer’s Disease. Front. Neurol. 2018, 9, 1–16. [Google Scholar] [CrossRef]
- Becerril-Ortega, J.; Bordji, K.; Fréret, T.; Rush, T.; Buisson, A. Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer’s disease. Neurobiol. Aging 2014, 35, 2288–2301. [Google Scholar] [CrossRef] [PubMed]
- Martinez, F.O.; Gordon, S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 2014, 6, 13. [Google Scholar] [CrossRef] [Green Version]
- Floden, A.M.; Li, S.; Combs, C.K. β-Amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors. J. Neurosci. 2005, 25, 2566–2575. [Google Scholar] [CrossRef] [PubMed]
- Brown, G.C.; Neher, J.J. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol. Neurobiol. 2010, 41, 242–247. [Google Scholar] [CrossRef] [PubMed]
- Orihuela, R.; McPherson, C.A.; Harry, G.J. Microglial M1/M2 polarization and metabolic states. Br. J. Pharmacol. 2016, 173, 649–665. [Google Scholar] [CrossRef] [PubMed]
- Johnson, E.E.; Wessling-Resnick, M. Iron metabolism and the innate immune response to infection. Microbes Infect. 2012, 14, 207–216. [Google Scholar] [CrossRef] [Green Version]
- Nairz, M.; Haschka, D.; Demetz, E.; Weiss, G. Iron at the interface of immunity and infection. Front. Pharmacol. 2014, 5, 152–162. [Google Scholar] [CrossRef] [Green Version]
- Nakamura, K.; Kawakami, T.; Yamamoto, N.; Tomizawa, M.; Fujiwara, T.; Ishii, T.; Harigae, H.; Ogasawara, K. Activation of the NLRP3 inflammasome by cellular labile iron. Exp. Hematol. 2016, 44, 116–124. [Google Scholar] [CrossRef]
- Liddelow, S.A.; Guttenplan, K.A.; Clarke, L.E.; Bennett, F.C.; Bohlen, C.J.; Schirmer, L.; Bennett, M.L.; Münch, A.E.; Chung, W.-S.; Peterson, T.C.; et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017, 541, 481–487. [Google Scholar] [CrossRef]
- Liddelow, S.A.; Barres, B.A. Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity 2017, 46, 957–967. [Google Scholar] [CrossRef] [Green Version]
- You, L.H.; Yan, C.Z.; Zheng, B.J.; Ci, Y.Z.; Chang, S.Y.; Yu, P.; Gao, G.F.; Li, H.Y.; Dong, T.Y.; Chang, Y.Z. Astrocyte hepcidin is a key factor in LPS-induced neuronal apoptosis. Cell Death Dis. 2017, 8, e2676. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fakhoury, M. Microglia and astrocytes in Alzheimer’s disease: Implications for therapy. Curr. Neuropharmacol. 2018, 16, 508–518. [Google Scholar] [CrossRef]
- Darreh-Shori, T.; Vijayaraghavan, S.; Aeinehband, S.; Piehl, F.; Lindblom, R.P.F.; Nilsson, B.; Ekdahl, K.N.; Långström, B.; Almkvist, O.; Nordberg, A. Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer’s disease. Neurobiol. Aging 2013, 34, 2465–2481. [Google Scholar] [CrossRef]
- Kadir, A.; Marutle, A.; Gonzalez, D.; Schöll, M.; Almkvist, O.; Mousavi, M.; Mustafiz, T.; Darreh-Shori, T.; Nennesmo, I.; Nordberg, A. Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease. Brain 2011, 134, 301–317. [Google Scholar] [CrossRef] [PubMed]
- Zecca, L.; Youdim, M.B.H.; Riederer, P.; Connor, J.R.; Crichton, R.R. Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 2004, 5, 863–873. [Google Scholar] [CrossRef] [PubMed]
- Connor, J.R.; Menzies, S.L.; St. Martin, S.M.; Mufson, E.J. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J. Neurosci. Res. 1990, 27, 595–611. [Google Scholar] [CrossRef]
- Connor, J.R.; Snyder, B.S.; Beard, J.L.; Fine, R.E.; Mufson, E.J. Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer’s disease. J. Neurosci. Res. 1992, 31, 327–335. [Google Scholar] [CrossRef]
- Ramos, P.; Santos, A.; Pinto, N.R.; Mendes, R.; Magalhães, T.; Almeida, A. Iron levels in the human brain: A post-mortem study of anatomical region differences and age-related changes. J. Trace Elem. Med. Biol. 2014, 28, 13–17. [Google Scholar] [CrossRef] [PubMed]
- Ashraf, A.; Clark, M.; So, P.W. The aging of iron man. Front. Aging Neurosci. 2018, 10, 65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gaasch, J.A.; Lockman, P.R.; Geldenhuys, W.J.; Allen, D.D.; Van der Schyf, C.J. Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells. Neurochem. Res. 2007, 32, 1196–1208. [Google Scholar] [CrossRef] [PubMed]
- DeGregorio-Rocasolano, N.; Martí-Sistac, O.; Ponce, J.; Castelló-Ruiz, M.; Millán, M.; Guirao, V.; García-Yébenes, I.; Salom, J.B.; Ramos-Cabrer, P.; Alborch, E.; et al. Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage. Redox Biol. 2018, 15, 143–158. [Google Scholar] [CrossRef]
- Khan, A.I.; Liu, J.; Dutta, P. Iron transport kinetics through blood-brain barrier endothelial cells. Biochim. Biophys. Acta Gen. Subj. 2018, 1862, 1168–1179. [Google Scholar] [CrossRef] [PubMed]
- Gunshin, H.; Mackenzie, B.; Berger, U.V.; Gunshin, Y.; Romero, M.F.; Boron, W.F.; Nussberger, S.; Gollan, J.L.; Hediger, M.A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997, 388, 482–488. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Z.D.; Tan, E.-K. Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Mol. Neurodegener. 2017, 12, 75–87. [Google Scholar] [CrossRef] [PubMed]
- Pigeon, C.; Ilyin, G.; Courselaud, B.; Leroyer, P.; Turlin, B.; Brissot, P.; Loréal, O. A New Mouse Liver-specific Gene, Encoding a Protein Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed during Iron Overload. J. Biol. Chem. 2001, 276, 7811–7819. [Google Scholar] [CrossRef] [Green Version]
- Verga Falzacappa, M.V.; Vujic Spasic, M.; Kessler, R.; Stolte, J.; Hentze, M.W.; Muckenthaler, M.U. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007, 109, 353–358. [Google Scholar] [CrossRef] [Green Version]
- Brissot, P.; Pietrangelo, A.; Adams, P.C.; de Graaff, B.; McLaren, C.E.; Loréal, O. Haemochromatosis. Nat. Rev. Dis. Prim. 2018, 4, 18016–18031. [Google Scholar] [CrossRef]
- Holmes, C.; Cunningham, C.; Zotova, E.; Woolford, J.; Dean, C.; Kerr, S.; Culliford, D.; Perry, V.H. Systemic inflammation and disease progression in alzheimer disease. Neurology 2009, 73, 768–774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Erdei, J.; Tóth, A.; Balogh, E.; Nyakundi, B.B.; Bányai, E.; Ryffel, B.; Paragh, G.; Cordero, M.D.; Jeney, V. Induction of NLRP3 Inflammasome Activation by Heme in Human Endothelial Cells. Oxid. Med. Cell. Longev. 2018, 2018, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McCarthy, R.C.; Park, Y.; Kosman, D.J. sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep. 2014, 15, 809–815. [Google Scholar] [CrossRef] [Green Version]
- Wong, B.X.; Tsatsanis, A.; Lim, L.Q.; Adlard, P.A.; Bush, A.I.; Duce, J.A. Β-Amyloid Precursor Protein Does Not Possess Ferroxidase Activity But Does Stabilize the Cell Surface Ferrous Iron Exporter Ferroportin. PLoS ONE 2014, 9, 1–19. [Google Scholar] [CrossRef] [Green Version]
- Galzitskaya, O.V.; Galushko, E.I.; Selivanova, O.M. Studies of the Process of Amyloid Formation by Aβ Peptide. Biochem. 2018, 83, S62–S80. [Google Scholar] [CrossRef] [PubMed]
- Puig, K.L.; Combs, C.K. Expression and function of APP and its metabolites outside the central nervous system. Exp. Gerontol. 2013, 48, 608–611. [Google Scholar] [CrossRef] [Green Version]
- Matsui, T.; Ingelsson, M.; Fukumoto, H.; Ramasamy, K.; Kowa, H.; Frosch, M.P.; Irizarry, M.C.; Hyman, B.T. Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain Res. 2007, 1161, 116–123. [Google Scholar] [CrossRef]
- Tyan, S.H.; Shih, A.Y.J.; Walsh, J.J.; Maruyama, H.; Sarsoza, F.; Ku, L.; Eggert, S.; Hof, P.R.; Koo, E.H.; Dickstein, D.L. Amyloid precursor protein (APP) regulates synaptic structure and function. Mol. Cell. Neurosci. 2012, 51, 43–52. [Google Scholar] [CrossRef] [Green Version]
- Ling, Y.; Morgan, K.; Kalsheker, N. Amyloid precursor protein (APP) and the biology of proteolytic processing: Relevance to Alzheimer’s disease. Int. J. Biochem. Cell Biol. 2003, 35, 1505–1535. [Google Scholar] [CrossRef]
- Kojro, E.; Gimpl, G.; Lammich, S.; Marz, W.; Fahrenholz, F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the -secretase ADAM 10. Proc. Natl. Acad. Sci. USA 2001, 98, 5815–5820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vassar, R. Beta-Secretase Cleavage of Alzheimer’s Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE. Science 1999, 286, 735–741. [Google Scholar] [CrossRef] [Green Version]
- Poon, C.H.; Wang, Y.; Fung, M.-L.; Zhang, C.; Lim, L.W. Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications. Aging Dis. 2020, 11, 1235–1259. [Google Scholar] [CrossRef]
- Piccinelli, P.; Samuelsson, T. Evolution of the iron-responsive element. RNA 2007, 13, 952–966. [Google Scholar] [CrossRef] [Green Version]
- Gunshin, H.; Allerson, C.R.; Polycarpou-Schwarz, M.; Rofts, A.; Rogers, J.T.; Kishi, F.; Hentze, M.W.; Rouault, T.A.; Andrews, N.C.; Hediger, M.A. Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett. 2001, 509, 309–316. [Google Scholar] [CrossRef] [Green Version]
- Muckenthaler, M.U.; Galy, B.; Hentze, M.W. Systemic Iron Homeostasis and the Iron-Responsive Element/Iron-Regulatory Protein (IRE/IRP) Regulatory Network. Annu. Rev. Nutr. 2008, 28, 197–213. [Google Scholar] [CrossRef]
- Rogers, J.T.; Randall, J.D.; Cahill, C.M.; Eder, P.S.; Huang, X.; Gunshin, H.; Leiter, L.; McPhee, J.; Sarang, S.S.; Utsuki, T.; et al. An Iron-responsive Element Type II in the 5′-Untranslated Region of the Alzheimer’s Amyloid Precursor Protein Transcript. J. Biol. Chem. 2002, 277, 45518–45528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cho, H.-H.; Cahill, C.M.; Vanderburg, C.R.; Scherzer, C.R.; Wang, B.; Huang, X.; Rogers, J.T. Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1. J. Biol. Chem. 2010, 285, 31217–31232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zou, K.; Gong, J.S.; Yanagisawa, K.; Michikawa, M. A Novel Function of Monomeric Amyloid β-Protein Serving as an Antioxidant Molecule against Metal-Induced Oxidative Damage. J. Neurosci. 2002, 22, 4833–4841. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018, 14, 450–464. [Google Scholar] [CrossRef] [PubMed]
- Long, J.M.; Maloney, B.; Rogers, J.T.; Lahiri, D.K. Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5’-untranslated region: Implications in Alzheimer’s disease. Mol. Psychiatry 2019, 24, 345–363. [Google Scholar] [CrossRef] [Green Version]
- Lockridge, O. Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol. Ther. 2015, 148, 34–46. [Google Scholar] [CrossRef]
- Lockridge, O.; Bartels, C.F.; Vaughan, T.A.; Wong, C.K.; Norton, S.E.; Johnson, L.L. Complete amino acid sequence of human serum cholinesterase. J. Biol. Chem. 1987, 262, 549–557. [Google Scholar] [CrossRef]
- Johnson, G.; Moore, S.W. Why has butyrylcholinesterase been retained? Structural and functional diversification in a duplicated gene. Neurochem. Int. 2012, 61, 783–797. [Google Scholar] [CrossRef] [PubMed]
- Tiethof, A.K.; Richardson, J.R.; Hart, R.P. Knockdown of butyrylcholinesterase but not inhibition by chlorpyrifos alters early differentiation mechanisms in human neural stem cells. Toxics 2018, 6, 52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Darvesh, S.; Hopkins, D.A.; Geula, C. Neurobiology of butyrylcholinesterase. Nat. Rev. Neurosci. 2003, 4, 131–138. [Google Scholar] [CrossRef]
- Mesulam, M.-M.; Guillozet, A.; Shaw, P.; Levey, A.; Duysen, E.; Lockridge, O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 2002, 110, 627–639. [Google Scholar] [CrossRef]
- Darvesh, S.; Grantham, D.L.; Hopkins, D.A. Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation. J. Comp. Neurol. 1998, 393, 374–390. [Google Scholar] [CrossRef]
- Darvesh, S.; Hopkins, D.A. Differential distribution of butyrylcholinesterase and acetylcholinesterase in the human thalamus. J. Comp. Neurol. 2003, 463, 25–43. [Google Scholar] [CrossRef]
- Darreh-Shori, T.; Forsberg, A.; Modiri, N.; Andreasen, N.; Blennow, K.; Kamil, C.; Ahmed, H.; Almkvist, O.; Långström, B.; Nordberg, A. Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer’s disease in the brain in vivo. Neurobiol. Aging 2011, 32, e15–e32. [Google Scholar] [CrossRef]
- Darvesh, S.; Cash, M.K.; Reid, G.A.; Martin, E.; Mitnitski, A.; Geula, C. Butyrylcholinesterase Is Associated with β-Amyloid Plaques in the Transgenic APPSWE/PSEN1dE9 Mouse Model of Alzheimer Disease. J. Neuropathol. Exp. Neurol. 2012, 71, 2–14. [Google Scholar] [CrossRef] [Green Version]
- Reid, G.A.; Darvesh, S. Butyrylcholinesterase-knockout reduces brain deposition of fibrillar β-amyloid in an Alzheimer mouse model. Neuroscience 2015, 298, 424–435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mesulam, M.; Geula, C. Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia. Ann. Neurol. 1994, 36, 722–727. [Google Scholar] [CrossRef] [PubMed]
- Geula, C.; Mesulam, M.-M. Cholinesterases and the Pathology of Alzheimer Disease. Alzheimer Dis. Assoc. Disord. 1995, 9, 23–28. [Google Scholar] [CrossRef] [PubMed]
- Gómez-Ramos, P.; Bouras, C.; Morán, M.A. Ultrastructural localization of butyrylcholinesterase on neurofibrillary degeneration sites in the brains of aged and Alzheimer’s disease patients. Brain Res. 1994, 640, 17–24. [Google Scholar] [CrossRef]
- Guillozet, A.L.; Mesulam, M.-M.; Smiley, J.F.; Mash, D.C. Butyrylcholinesterase in the life cycle of amyloid plaques. Ann. Neurol. 1997, 42, 909–918. [Google Scholar] [CrossRef]
- Jasiecki, J.; Jońca, J.; Żuk, M.; Szczoczarz, A.; Janaszak-Jasiecka, A.; Lewandowski, K.; Waleron, K.; Wasąg, B. Activity and polymorphisms of butyrylcholinesterase in a Polish population. Chem. Biol. Interact. 2016, 259, 70–77. [Google Scholar] [CrossRef] [PubMed]
- Brissot, P.; Troadec, M.-B.; Loréal, O.; Brissot, E. Pathophysiology and classification of iron overload diseases; update 2018. Transfus. Clin. Biol. 2019, 26, 80–88. [Google Scholar] [CrossRef]
- Ganz, T. Erythropoietic regulators of iron metabolism. Free Radic. Biol. Med. 2019, 133, 69–74. [Google Scholar] [CrossRef]
- Elliott, S.; Pham, E.; Macdougall, I.C. Erythropoietins: A common mechanism of action. Exp. Hematol. 2008, 36, 1573–1584. [Google Scholar] [CrossRef]
- Furlow, P.W.; Percy, M.J.; Sutherland, S.; Bierl, C.; McMullin, M.F.; Master, S.R.; Lappin, T.R.J.; Lee, F.S. Erythrocytosis-associated HIF-2α Mutations Demonstrate a Critical Role for Residues C-terminal to the Hydroxylacceptor Proline. J. Biol. Chem. 2009, 284, 9050–9058. [Google Scholar] [CrossRef] [Green Version]
- Zimmer, M.; Ebert, B.L.; Neil, C.; Brenner, K.; Papaioannou, I.; Melas, A.; Tolliday, N.; Lamb, J.; Pantopoulos, K.; Golub, T.; et al. Small-Molecule Inhibitors of HIF-2a Translation Link Its 5′UTR Iron-Responsive Element to Oxygen Sensing. Mol. Cell 2008, 32, 838–848. [Google Scholar] [CrossRef] [Green Version]
- Lappin, T.R.; Lee, F.S. Update on mutations in the HIF: EPO pathway and their role in erythrocytosis. Blood Rev. 2019, 37, 100590–100599. [Google Scholar] [CrossRef] [PubMed]
- Campillos, M.; Cases, I.; Hentze, M.W.; Sanchez, M. SIREs: Searching for iron-responsive elements. Nucleic Acids Res. 2010, 38, 360–367. [Google Scholar] [CrossRef] [Green Version]
- Jasiecki, J.; Limon-Sztencel, A.; Żuk, M.; Chmara, M.; Cysewski, D.; Limon, J.; Wasąg, B. Synergy between the alteration in the N-terminal region of butyrylcholinesterase K variant and apolipoprotein E4 in late-onset Alzheimer’s disease. Sci. Rep. 2019, 9, 5223. [Google Scholar] [CrossRef] [PubMed]
- Jońca, J.; Zuk, M.; Wasag, B.; Janaszak-Jasiecka, A.; Lewandowski, K.; Wielgomas, B.; Waleron, K.; Jasiecki, J. New insights into butyrylcholinesterase activity assay: Serum dilution factor as a crucial parameter. PLoS ONE 2015, 10, e0139480. [Google Scholar] [CrossRef]
- Liu, J.-L.; Fan, Y.-G.; Yang, Z.-S.; Wang, Z.-Y.; Guo, C. Iron and Alzheimer’s Disease: From Pathogenesis to Therapeutic Implications. Front. Neurosci. 2018, 12, 632. [Google Scholar] [CrossRef] [Green Version]
- Nuñez, M.T.; Chana-Cuevas, P. New perspectives in iron chelation therapy for the treatment of neurodegenerative diseases. Pharmaceuticals 2018, 11, 109. [Google Scholar] [CrossRef] [Green Version]
- Guo, C.; Wang, T.; Zheng, W.; Shan, Z.-Y.; Teng, W.-P.; Wang, Z.-Y. Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Aging 2013, 34, 562–575. [Google Scholar] [CrossRef]
- Banerjee, P.; Sahoo, A.; Anand, S.; Ganguly, A.; Righi, G.; Bovicelli, P.; Saso, L.; Chakrabarti, S. Multiple Mechanisms of Iron-Induced Amyloid Beta-Peptide Accumulation in SHSY5Y Cells: Protective Action of Negletein. NeuroMol. Med. 2014, 16, 787–798. [Google Scholar] [CrossRef]
- McLachlan, D.R.C.; Kruck, T.P.A.; Kalow, W.; Andrews, D.F.; Dalton, A.J.; Bell, M.Y.; Smith, W.L. Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 1991, 337, 1304–1308. [Google Scholar] [CrossRef]
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Jasiecki, J.; Targońska, M.; Wasąg, B. The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis. Int. J. Mol. Sci. 2021, 22, 2033. https://doi.org/10.3390/ijms22042033
Jasiecki J, Targońska M, Wasąg B. The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis. International Journal of Molecular Sciences. 2021; 22(4):2033. https://doi.org/10.3390/ijms22042033
Chicago/Turabian StyleJasiecki, Jacek, Monika Targońska, and Bartosz Wasąg. 2021. "The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis" International Journal of Molecular Sciences 22, no. 4: 2033. https://doi.org/10.3390/ijms22042033