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Removal of p75 Neurotrophin Receptor Expression from Cholinergic Basal Forebrain Neurons Reduces Amyloid-β Plaque Deposition and Cognitive Impairment in Aged APP/PS1 Mice

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Abstract

The degeneration of cholinergic basal forebrain (cBF) neurons in Alzheimer’s disease (AD) leads to the cognitive impairment associated with this condition. cBF neurons express the p75 neurotrophin receptor (p75NTR), which mediates cell death, and the extracellular domain of p75NTR can bind to amyloid beta (Aβ) and promote its degradation. Here, we investigated the contribution of cBF neuronal p75NTR to the progression of AD by removing p75NTR from cholinergic neurons in the APP/PS1 familial AD mouse strain. Conditional loss of p75NTR slowed cognitive decline and reduced both Aβ accumulation into plaques and gliosis. Expression of the amyloid protein precursor and its cleavage enzymes ADAM10 and BACE1 were unchanged. There was also no upregulation of p75NTR in non-cholinergic cell types. This indicates that a direct interaction between cBF-expressed p75NTR and Aβ does not contribute significantly to the regulation of Aβ load. Rather, loss of p75NTR from cBF neurons, which results in increased cholinergic innervation of the cortex, appears to regulate alternative, more dominant, Aβ clearance mechanisms.

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References

  1. Whitehouse PJ, Struble RG, Clark AW, Price DL (1982) Alzheimer disease: plaques, tangles, and the basal forebrain. Ann Neurol 12(5):494. https://doi.org/10.1002/ana.410120517

    Article  CAS  PubMed  Google Scholar 

  2. Grothe MJ, Schuster C, Bauer F, Heinsen H, Prudlo J, Teipel SJ (2014) Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia. J Neurol 261(10):1939–1948. https://doi.org/10.1007/s00415-014-7439-z

    Article  PubMed  Google Scholar 

  3. Grothe M, Heinsen H, Teipel S (2013) Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer’s disease. Neurobiol Aging 34(4):1210–1220. https://doi.org/10.1016/j.neurobiolaging.2012.10.018

    Article  CAS  PubMed  Google Scholar 

  4. Mufson EJ, Ma SY, Dills J, Cochran EJ, Leurgans S, Wuu J, Bennett DA, Jaffar S et al (2002) Loss of basal forebrain p75NTR immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 443(2):136–153

    Article  CAS  PubMed  Google Scholar 

  5. Schmitz TW, Nathan Spreng R, Alzheimer’s Disease Neuroimaging I (2016) Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology. Nat Commun 7:13249. https://doi.org/10.1038/ncomms13249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grothe M, Zaborszky L, Atienza M, Gil-Neciga E, Rodriguez-Romero R, Teipel SJ, Amunts K, Suarez-Gonzalez A et al (2010) Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer’s disease. Cereb Cortex 20(7):1685–1695. https://doi.org/10.1093/cercor/bhp232

    Article  PubMed  Google Scholar 

  7. Grothe MJ, Ewers M, Krause B, Heinsen H, Teipel SJ, Alzheimer's Disease Neuroimaging I (2014) Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement 10(5 Suppl):S344–S353. https://doi.org/10.1016/j.jalz.2013.09.011

    Article  PubMed  PubMed Central  Google Scholar 

  8. Teipel S, Heinsen H, Amaro E Jr, Grinberg LT, Krause B, Grothe M, Alzheimer's Disease Neuroimaging I (2014) Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer’s disease. Neurobiol Aging 35(3):482–491. https://doi.org/10.1016/j.neurobiolaging.2013.09.029

    Article  CAS  PubMed  Google Scholar 

  9. Teipel SJ, Meindl T, Grinberg L, Grothe M, Cantero JL, Reiser MF, Moller HJ, Heinsen H et al (2011) The cholinergic system in mild cognitive impairment and Alzheimer's disease: An in vivo MRI and DTI study. Hum Brain Mapp 32(9):1349–1362. https://doi.org/10.1002/hbm.21111

    Article  PubMed  Google Scholar 

  10. Kerbler GM, Fripp J, Rowe CC, Villemagne VL, Salvado O, Rose S, Coulson EJ, Alzheimer’s Disease Neuroimaging I (2015) Basal forebrain atrophy correlates with amyloid β burden in Alzheimer’s disease. NeuroImage Clin 7:105–113. https://doi.org/10.1016/j.nicl.2014.11.015

    Article  PubMed  Google Scholar 

  11. Kerbler GM, Nedelska Z, Fripp J, Laczo J, Vyhnalek M, Lisy J, Hamlin AS, Rose S et al (2015) Basal forebrain atrophy contributes to allocentric navigation impairment in Alzheimer’s disease patients. Front Aging Neurosci 7:185. https://doi.org/10.3389/fnagi.2015.00185

    Article  PubMed  PubMed Central  Google Scholar 

  12. Laursen B, Mork A, Plath N, Kristiansen U, Bastlund JF (2013) Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice. Behav Brain Res 240:146–152. https://doi.org/10.1016/j.bbr.2012.11.012

    Article  CAS  PubMed  Google Scholar 

  13. Gil-Bea FJ, Gerenu G, Aisa B, Kirazov LP, Schliebs R, Ramirez MJ (2012) Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice. Neurobiol Dis 48(3):439–446. https://doi.org/10.1016/j.nbd.2012.06.020

    Article  CAS  PubMed  Google Scholar 

  14. Hartig W, Saul A, Kacza J, Grosche J, Goldhammer S, Michalski D, Wirths O (2014) Immunolesion-induced loss of cholinergic projection neurones promotes β-amyloidosis and tau hyperphosphorylation in the hippocampus of triple-transgenic mice. Neuropathol Appl Neurobiol 40(2):106–120. https://doi.org/10.1111/nan.12050

    Article  CAS  PubMed  Google Scholar 

  15. Ramos-Rodriguez JJ, Pacheco-Herrero M, Thyssen D, Murillo-Carretero MI, Berrocoso E, Spires-Jones TL, Bacskai BJ, Garcia-Alloza M (2013) Rapid β-amyloid deposition and cognitive impairment after cholinergic denervation in APP/PS1 mice. J Neuropathol Exp Neurol 72(4):272–285. https://doi.org/10.1097/NEN.0b013e318288a8dd

    Article  CAS  PubMed  Google Scholar 

  16. Turnbull MT, Boskovic Z, Coulson EJ (2018) Acute down-regulation of BDNF signaling does not replicate exacerbated amyloid-β levels and cognitive impairment induced by cholinergic basal forebrain lesion. Front Mol Neurosci 11:51. https://doi.org/10.3389/fnmol.2018.00051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hernandez CM, Kayed R, Zheng H, Sweatt JD, Dineley KT (2010) Loss of α7 nicotinic receptors enhances β-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer’s disease. J Neurosci 30(7):2442–2453. https://doi.org/10.1523/JNEUROSCI.5038-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) β-amyloid1-42 induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28(15):3941–3946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Knowles JK, Simmons DA, Nguyen TV, Vander Griend L, Xie Y, Zhang H, Yang T, Pollak J et al (2013) A small molecule p75 ligand prevents cognitive deficits and neurite degeneration in an Alzheimer’s mouse model. Neurobiol Aging 34:2052–2063. https://doi.org/10.1016/j.neurobiolaging.2013.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Knowles JK, Rajadas J, Nguyen TV, Yang T, LeMieux MC, Vander Griend L, Ishikawa C, Massa SM et al (2009) The p75 neurotrophin receptor promotes amyloid-β1-42-induced neuritic dystrophy in vitro and in vivo. J Neurosci 29(34):10627–10637. https://doi.org/10.1523/JNEUROSCI.0620-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ovsepian SV, Antyborzec I, O'Leary VB, Zaborszky L, Herms J, Oliver Dolly J (2014) Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons. Brain Struct Funct 219(5):1527–1541. https://doi.org/10.1007/s00429-013-0583-x

    Article  CAS  PubMed  Google Scholar 

  22. Ovsepian SV, Herms J (2013) Drain of the brain: low-affinity p75 neurotrophin receptor affords a molecular sink for clearance of cortical amyloid β by the cholinergic modulator system. Neurobiol Aging 34(11):2517–2524. https://doi.org/10.1016/j.neurobiolaging.2013.05.005

    Article  CAS  PubMed  Google Scholar 

  23. Ibanez CF, Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35(7):431–440. https://doi.org/10.1016/j.tins.2012.03.007

    Article  CAS  PubMed  Google Scholar 

  24. Dechant G, Barde YA (2002) The neurotrophin receptor p75NTR: novel functions and implications for diseases of the nervous system. Nat Neurosci 5(11):1131–1136

    Article  CAS  PubMed  Google Scholar 

  25. Coulson EJ, May LM, Sykes AM, Hamlin AS (2009) The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer's disease. Neuroscientist 15(4):317–323. https://doi.org/10.1177/1073858408331376

    Article  CAS  PubMed  Google Scholar 

  26. Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE, Gilchrest BA (1997) Binding of β-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest 100(9):2333–2340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arble BL, Stewart KB, Gilchrest BA (2002) Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem 277(10):7720–7725

    Article  CAS  PubMed  Google Scholar 

  28. Wang YR, Wang J, Liu YH, Hu GL, Gao CY, Wang YJ, Zhou XF, Zeng F (2018) Cysteine-rich repeat domains 2 and 4 are amyloid-β binding domains of neurotrophin receptor p75NTR and potential targets to block amyloid-β neurotoxicity. J Alzheimers Dis 63(1):139–147. https://doi.org/10.3233/JAD-171012

    Article  CAS  PubMed  Google Scholar 

  29. Rabizadeh S, Bitler CM, Butcher LL, Bredesen DE (1994) Expression of the low-affinity nerve growth factor receptor enhances β-amyloid peptide toxicity. Proc Natl Acad Sci U S A 91(22):10703–10706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. May LM, Anggono V, Gooch HM, Jang SE, Matusica D, Kerbler GM, Meunier FA, Sah P et al (2017) G-protein-coupled inwardly rectifying potassium (GIRK) channel activation by the p75 neurotrophin receptor is required for amyloid β toxicity. Front Neurosci 11:455. https://doi.org/10.3389/fnins.2017.00455

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yang T, Knowles JK, Lu Q, Zhang H, Arancio O, Moore LA, Chang T, Wang Q et al (2008) Small molecule, non-peptide p75 ligands inhibit Aβ-induced neurodegeneration and synaptic impairment. PLoS One 3(11):e3604. https://doi.org/10.1371/journal.pone.0003604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Costantini C, Rossi F, Formaggio E, Bernardoni R, Cecconi D, Della-Bianca V (2005) Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death. J Mol Neurosci 25(2):141–156

    Article  CAS  PubMed  Google Scholar 

  33. Kuner P, Schubenel R, Hertel C (1998) β-amyloid binds to p75NTR and activates NFκB in human neuroblastoma cells. J Neurosci Res 54(6):798–804

    Article  CAS  PubMed  Google Scholar 

  34. Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S (2013) A DR6/p75NTR complex is responsible for β-amyloid-induced cortical neuron death. Cell Death Dis 4:e579. https://doi.org/10.1038/cddis.2013.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang YJ, Wang X, Lu JJ, Li QX, Gao CY, Liu XH, Sun Y, Yang M et al (2011) p75NTR regulates Aβ deposition by increasing Aβ production but inhibiting Aβ aggregation with its extracellular domain. J Neurosci 31(6):2292–2304. https://doi.org/10.1523/JNEUROSCI.2733-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nguyen TV, Shen L, Vander Griend L, Quach LN, Belichenko NP, Saw N, Yang T, Shamloo M et al (2014) Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPP(L/S) transgenic mice. J Alzheimers Dis 42(2):459–483. https://doi.org/10.3233/JAD-140036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Murphy M, Wilson YM, Vargas E, Munro KM, Smith B, Huang A, Li QX, Xiao J et al (2015) Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease. Neurobiol Aging 36(2):740–752. https://doi.org/10.1016/j.neurobiolaging.2014.09.014

    Article  CAS  PubMed  Google Scholar 

  38. Jian C, Zou D, Luo C, Liu X, Meng L, Huang J, Li X, Huang R et al (2016) Cognitive deficits are ameliorated by reduction in amyloid β accumulation in Tg2576/p75NTR+/− mice. Life Sci 155:167–173. https://doi.org/10.1016/j.lfs.2016.05.011

    Article  CAS  PubMed  Google Scholar 

  39. Boskovic Z, Alfonsi F, Rumballe BA, Fonseka S, Windels F, Coulson EJ (2014) The role of p75NTR in cholinergic basal forebrain structure and function. J Neurosci 34(39):13033–13038. https://doi.org/10.1523/JNEUROSCI.2364-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hamlin AS, Windels F, Boskovic Z, Sah P, Coulson EJ (2013) Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation. PLoS One 8(1):e53472. https://doi.org/10.1371/journal.pone.0053472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Greferath U, Bennie A, Kourakis A, Bartlett PF, Murphy M, Barrett GL (2000) Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice. Eur J Neurosci 12(3):885–893

    Article  CAS  PubMed  Google Scholar 

  42. Longo FM, Massa SM (2013) Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov 12(7):507–525

    Article  PubMed  Google Scholar 

  43. Zeng F, Lu JJ, Zhou XF, Wang YJ (2011) Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem Pharmacol 82(10):1500–1509. https://doi.org/10.1016/j.bcp.2011.06.040

    Article  CAS  PubMed  Google Scholar 

  44. Mufson EJ, Counts SE, Perez SE, Ginsberg SD (2008) Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 8(11):1703–1718. https://doi.org/10.1586/14737175.8.11.1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shepheard SR, Wuu J, Cardoso M, Wiklendt L, Dinning PG, Chataway T, Schultz D, Benatar M et al (2017) Urinary p75ECD: a prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology 88(12):1137–1143. https://doi.org/10.1212/WNL.0000000000003741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jiao SS, Bu XL, Liu YH, Wang QH, Liu CH, Yao XQ, Zhou XF, Wang YJ (2015) Differential levels of p75NTR ectodomain in CSF and blood in patients with Alzheimer’s disease: a novel diagnostic marker. Transl Psychiatry 5:e650. https://doi.org/10.1038/tp.2015.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhou XF, Wang YJ (2011) The p75NTR extracellular domain: a potential molecule regulating the solubility and removal of amyloid-β. Prion 5(3):161–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang QH, Wang YR, Zhang T, Jiao SS, Liu YH, Zeng F, Li J, Yao XQ et al (2016) Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer’s disease-like pathologies in APP/PS1 transgenic mice. J Neurochem 138(1):163–173. https://doi.org/10.1111/jnc.13616

    Article  CAS  PubMed  Google Scholar 

  49. Yao XQ, Jiao SS, Saadipour K, Zeng F, Wang QH, Zhu C, Shen LL, Zeng GH et al (2015) p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-β toxicity in the brain of Alzheimer’s disease. Mol Psychiatry 20(11):1301–1310. https://doi.org/10.1038/mp.2015.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cimadevilla JM, Kaminsky Y, Fenton A, Bures J (2000) Passive and active place avoidance as a tool of spatial memory research in rats. J Neurosci Meth 102(2):155–164

    Article  CAS  Google Scholar 

  51. Wesierska M, Dockery C, Fenton AA (2005) Beyond memory, navigation, and inhibition: behavioral evidence for hippocampus-dependent cognitive coordination in the rat. J Neurosci 25(9):2413–2419. https://doi.org/10.1523/JNEUROSCI.3962-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shepheard SR, Chataway T, Schultz DW, Rush RA, Rogers ML (2014) The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis. PLoS One 9(1):e87398. https://doi.org/10.1371/journal.pone.0087398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Matusica D, Alfonsi F, Turner BJ, Butler TJ, Shepheard SR, Rogers ML, Skeldal S, Underwood CK et al (2016) Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment. J Cell Sci 129(3):517–530. https://doi.org/10.1242/jcs.173864

    Article  CAS  PubMed  Google Scholar 

  54. Vukovic J, Borlikova GG, Ruitenberg MJ, Robinson GJ, Sullivan RK, Walker TL, Bartlett PF (2013) Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering. J Neurosci 33(15):6603–6613. https://doi.org/10.1523/JNEUROSCI.3064-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mufson EJ, Kordower JH (1992) Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer disease. Proc Natl Acad Sci U S A 89(2):569–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chakravarthy B, Gaudet C, Menard M, Atkinson T, Brown L, Laferla FM, Armato U, Whitfield J (2010) Amyloid-β peptides stimulate the expression of the p75NTR neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. J Alz Dis 19(3):915–925. https://doi.org/10.3233/JAD-2010-1288

    Article  CAS  Google Scholar 

  57. Perini G, Della-Bianca V, Politi V, Della Valle G, Dal-Pra I, Rossi F, Armato U (2002) Role of p75 neurotrophin receptor in the neurotoxicity by β-amyloid peptides and synergistic effect of inflammatory cytokines. J Exp Med 195(7):907–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jaffar S, Counts SE, Ma SY, Dadko E, Gordon MN, Morgan D, Mufson EJ (2001) Neuropathology of mice carrying mutant APPswe and/or PS1M146L transgenes: alterations in the p75NTR cholinergic basal forebrain septohippocampal pathway. Exp Neurol 170(2):227–243

    Article  CAS  PubMed  Google Scholar 

  59. Catts VS, Al-Menhali N, Burne TH, Colditz MJ, Coulson EJ (2008) The p75 neurotrophin receptor regulates hippocampal neurogenesis and related behaviours. Eur J Neurosci 28(5):883–892. https://doi.org/10.1111/j.1460-9568.2008.06390.x

    Article  PubMed  Google Scholar 

  60. Boskovic Z, Milne M, Qian L, Clifton H, McGovern AE, Turnbull MT, Mazzone SB, Coulson EJ (2018) Cholinergic basal forebrain neurons regulate fear extinction consolidation through p75 neurotrophin receptor signaling. Transl Psychiatry 8:199. https://doi.org/10.1038/s41398-018-0248-x, https://www.nature.com/articles/s41398-018-0248-x

  61. Rosch H, Schweigreiter R, Bonhoeffer T, Barde YA, Korte M (2005) The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc Natl Acad Sci U S A 102(20):7362–7367

    Article  PubMed  PubMed Central  Google Scholar 

  62. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8(8):1069–1077

    Article  CAS  PubMed  Google Scholar 

  63. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D et al (2000) High-level neuronal expression of Aβ1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20(11):4050–4058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Agholme L, Hallbeck M (2014) Getting rid of intracellular Aβ - loss of cellular degradation leads to transfer between connected neurons. Curr Pharm Des 20(15):2458–2468

    Article  CAS  PubMed  Google Scholar 

  65. Zuroff L, Daley D, Black KL, Koronyo-Hamaoui M (2017) Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci 74(12):2167–2201. https://doi.org/10.1007/s00018-017-2463-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Solito E, Sastre M (2012) Microglia function in Alzheimer’s disease. Front Pharmacol 3:14. https://doi.org/10.3389/fphar.2012.00014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49(5):671–682. https://doi.org/10.1016/j.neuron.2006.01.020

    Article  CAS  PubMed  Google Scholar 

  68. Davis AA, Fritz JJ, Wess J, Lah JJ, Levey AI (2010) Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci 30(12):4190–4196. https://doi.org/10.1523/JNEUROSCI.6393-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kolisnyk B, Al-Onaizi MA, Xu J, Parfitt GM, Ostapchenko VG, Hanin G, Soreq H, Prado MA et al (2016) Cholinergic regulation of hnRNPA2/B1 translation by M1 muscarinic receptors. J Neurosci 36(23):6287–6296. https://doi.org/10.1523/JNEUROSCI.4614-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kolisnyk B, Al-Onaizi M, Soreq L, Barbash S, Bekenstein U, Haberman N, Hanin G, Kish MT et al (2017) Cholinergic surveillance over hippocampal RNA metabolism and Alzheimer’s-like pathology. Cereb Cortex 27(7):3553–3567. https://doi.org/10.1093/cercor/bhw177

    Article  PubMed  Google Scholar 

  71. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147):147ra111. https://doi.org/10.1126/scitranslmed.3003748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Peng W, Achariyar TM, Li B, Liao Y, Mestre H, Hitomi E, Regan S, Kasper T et al (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis 93:215–225. https://doi.org/10.1016/j.nbd.2016.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hamner JW, Tan CO, Tzeng YC, Taylor JA (2012) Cholinergic control of the cerebral vasculature in humans. J Physiol 590(24):6343–6352. https://doi.org/10.1113/jphysiol.2012.245100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu Y, Studzinski C, Beckett T, Murphy MP, Klein RL, Hersh LB (2010) Circulating neprilysin clears brain amyloid. Mol Cell Neurosci 45(2):101–107. https://doi.org/10.1016/j.mcn.2010.05.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank other members of our laboratories, particularly Bree Rumballe (Coulson Lab) and Micell Cardoso (Rogers Lab) for administrative and technical assistance respectively, as well as helpful discussions, Luke Hammond for assistance with microscopy analysis and Rowan Tweedale for critical reading and editing of the manuscript.

Funding

This work was supported by the Australian National Health and Medical Research Council of Australia [project grant 1049236 to EJC; project grant 1139469 and Boosting Dementia Fellowship 1139469 to RM], and a Motor Neuron Disease Australia Grant in Aid [MLR,SS].

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Authors and Affiliations

  1. Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD, 4072, Australia

    Lei Qian, Michael R. Milne, Rodrigo Medeiros & Elizabeth J. Coulson

  2. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia

    Lei Qian, Michael R. Milne & Elizabeth J. Coulson

  3. Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, SA, 5001, Australia

    Stephanie Shepheard & Mary-Louise Rogers

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  1. Lei Qian
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Correspondence to Elizabeth J. Coulson.

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All procedures were approved by the University of Queensland Animal Ethics Committee and conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.

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Qian, L., Milne, M.R., Shepheard, S. et al. Removal of p75 Neurotrophin Receptor Expression from Cholinergic Basal Forebrain Neurons Reduces Amyloid-β Plaque Deposition and Cognitive Impairment in Aged APP/PS1 Mice. Mol Neurobiol 56, 4639–4652 (2019). https://doi.org/10.1007/s12035-018-1404-2

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  • DOI: https://doi.org/10.1007/s12035-018-1404-2

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