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p75NTR: A Molecule with Multiple Functions in Amyloid-β Metabolism and Neurotoxicity

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Handbook of Neurotoxicity

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Amyloid-β (Aβ) accumulation and the downstream pathological events, such as neurofibrillary tangles, neuron loss, neurite degeneration, as well as cognitive dysfunction, are hallmarks of the disease. Until now, the pathogenesis of AD is not fully understood, and no disease-modifying interventions are currently available. Recent studies suggest that the neurotrophin receptor p75 (p75NTR), a receptor for Aβ, is a key factor involved in AD pathogenesis. While more potential functions of p75NTR remain to be discovered, this review tried to elaborate the diverse roles of p75NTR in AD, providing a promising therapeutic target for the disease.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

Aβ:

Amyloid-β

BACE1:

Beta-site amyloid precursor protein cleaving enzyme-1

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

CNS:

Central nervous system

CRD:

Cysteine-rich domain

CSF:

Cerebrospinal fluid

CTF:

C-terminal fragment

DRG:

Dorsal root ganglion

EAE:

Experimental allergic encephalomyelitis

ECD:

Extracellular domain

GCP:

Granule cell progenitor

HD:

Huntington’s disease

ICD:

Intracellular domain

IGF-1R:

Growth factor 1 receptor

LTD:

Long-term depression

MAG:

Myelin-associated glycoprotein

NBM:

Nucleus basalis of Meynert

NFT:

Neurofibrillary tangle

NT:

Neurotrophin

p75NTR:

The neurotrophin receptor p75

PNS:

Peripheral nervous system

RGC:

Retinal ganglion cell

TACE:

Tumor necrosis factor-alpha converting enzyme

TNF:

Tumor necrosis factor

Trk:

Tropomyosin receptor kinase

References

  • Allard, S., Jacobs, M. L., Do Carmo, S., & Cuello, A. C. (2018). Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons. Neurobiology of Aging, 67, 10–20.

    Article  CAS  Google Scholar 

  • Bai, Y., Dergham, P., Nedev, H., Xu, J., Galan, A., Rivera, J. C., Zhihua, S., Mehta, H. M., Woo, S. B., Sarunic, M. V., Neet, K. E., & Saragovi, H. U. (2010). Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism. The Journal of Biological Chemistry, 285, 39392–39400.

    Article  CAS  Google Scholar 

  • Bengoechea, T. G., Chen, Z., O’leary, D., Masliah, E., & Lee, K. F. (2009). p75 reduces beta-amyloid-induced sympathetic innervation deficits in an Alzheimer’s disease mouse model. Proceedings of the National Academy of Sciences of the United States of America, 106, 7870–7875.

    Article  CAS  Google Scholar 

  • Brito, V., Puigdellivol, M., Giralt, A., Del Toro, D., Alberch, J., & GINES, S. (2013). Imbalance of p75(NTR)/TrkB protein expression in Huntington’s disease: Implication for neuroprotective therapies. Cell Death & Disease, 4, e595.

    Article  CAS  Google Scholar 

  • Brito, V., Giralt, A., Enriquez-Barreto, L., Puigdellivol, M., Suelves, N., Zamora-Moratalla, A., Ballesteros, J. J., Martin, E. D., Dominguez-Iturza, N., Morales, M., Alberch, J., & Gines, S. (2014). Neurotrophin receptor p75(NTR) mediates Huntington’s disease-associated synaptic and memory dysfunction. The Journal of Clinical Investigation, 124, 4411–4428.

    Article  CAS  Google Scholar 

  • Chakravarthy, B., Gaudet, C., Menard, M., Atkinson, T., Brown, L., Laferla, F. M., Armato, U., & Whitfield, J. (2010). Amyloid-beta peptides stimulate the expression of the p75NTR neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. Journal of Alzheimer’s Disease, 19, 915–925.

    Article  CAS  Google Scholar 

  • Chakravarthy, B., Menard, M., Ito, S., Gaudet, C., Dal Pra, I., Armato, U., & Whitfield, J. (2012). Hippocampal membrane-associated p75NTR levels are increased in Alzheimer’s disease. Journal of Alzheimer’s Disease, 30, 675–684.

    Article  CAS  Google Scholar 

  • Coulson, D. T., Beyer, N., Quinn, J. G., Brockbank, S., Hellemans, J., Irvine, G. B., Ravid, R., & Johnston, J. A. (2010). BACE1 mRNA expression in Alzheimer’s disease postmortem brain tissue. Journal of Alzheimer’s Disease, 22, 1111–1122.

    Article  CAS  Google Scholar 

  • Coulson, E. J., Simmons, D. A., Knowles, J. K., Belichenko, N. P., Banerjee, G., Finkle, C., Massa, S. M., & Longo, F. M. (2014). A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer’s disease mouse models with mid- to late-stage disease progression. PLoS One, 9, e102136.

    Google Scholar 

  • Cragnolini, A. B., Volosin, M., Huang, Y., & Friedman, W. J. (2012). Nerve growth factor induces cell cycle arrest of astrocytes. Developmental Neurobiology, 72, 766–776.

    Article  CAS  Google Scholar 

  • Dias Bda, C., Jovanovic, K., Gonsalves, D., & Weiss, S. F. (2011). Structural and mechanistic commonalities of amyloid-beta and the prion protein. Prion, 5, 126–137.

    Article  Google Scholar 

  • Finan, G. M., Okada, H., & Kim, T. W. (2011). BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. Journal of Biological Chemistry, 286, 12602–12616.

    Article  CAS  Google Scholar 

  • Gao, C., Zhang, L., Sun, D., Li, J., Yao, X., Zhou, H., & Wang, Y. (2017). Roles of p75NTR in maintaining brain hemostasis and the implications for p75NTR-targeted therapies. Current Alzheimer Research, 14, 554–561.

    Article  CAS  Google Scholar 

  • Geetha, T., Zheng, C., Mcgregor, W. C., Douglas White, B., Diaz-Meco, M. T., Moscat, J., & Babu, J. R. (2012). TRAF6 and p62 inhibit amyloid beta-induced neuronal death through p75 neurotrophin receptor. Neurochemistry International, 61, 1289–1293.

    Google Scholar 

  • Iijima, K. M., Hasebe, N., Fujita, Y., Ueno, M., Yoshimura, K., Fujino, Y., & Yamashita, T. (2013). Soluble β-amyloid precursor protein alpha binds to p75 neurotrophin receptor to promote neurite outgrowth. PLoS One, 8, e82321.

    Google Scholar 

  • Ioannou, M. S., & Fahnestock, M. (2017). ProNGF, but not NGF, switches from neurotrophic to apoptotic activity in response to reductions in TrkA receptor levels. International Journal of Molecular Sciences, 18, 599.

    Google Scholar 

  • Ito, S., Menard, M., Atkinson, T., Gaudet, C., Brown, L., Whitfield, J., & Chakravarthy, B. (2012). Involvement of insulin-like growth factor 1 receptor signaling in the amyloid-beta peptide oligomers-induced p75 neurotrophin receptor protein expression in mouse hippocampus. Journal of Alzheimer’s Disease, 31, 493–506.

    Article  CAS  Google Scholar 

  • Jian, C., Zou, D., Luo, C., Liu, X., Meng, L., Huang, J., Li, X., Huang, R., & Wu, Y. (2016). Cognitive deficits are ameliorated by reduction in amyloid beta accumulation in Tg2576/p75(NTR+/−) mice. Life Sciences, 155, 167–173.

    Article  CAS  Google Scholar 

  • Knowles, J. K., Rajadas, J., Nguyen, T. V., Yang, T., Lemieux, M. C., Vander Griend, L., Ishikawa, C., Massa, S. M., Wyss-Coray, T., & Longo, F. M. (2009). The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. The Journal of Neuroscience, 29, 10627–10637.

    Article  CAS  Google Scholar 

  • Knowles, J. K., Simmons, D. A., Nguyen, T. V., Vander Griend, L., Xie, Y., Zhang, H., Yang, T., Pollak, J., Chang, T., Arancio, O., Buckwalter, M. S., Wyss-Coray, T., Massa, S. M., & Longo, F. M. (2013). Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer’s mouse model. Neurobiology of Aging, 34, 2052–2063.

    Article  CAS  Google Scholar 

  • Kraemer, B. R., Snow, J. P., Vollbrecht, P., Pathak, A., Valentine, W. M., Deutch, A. Y., & Carter, B. D. (2014a). A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. The Journal of Biological Chemistry, 289, 21205–21216.

    Article  Google Scholar 

  • Kraemer, B. R., Yoon, S. O., & Carter, B. D. (2014b). The biological functions and signaling mechanisms of the p75 neurotrophin receptor. Handbook of Experimental Pharmacology, 220, 121–164.

    Article  CAS  Google Scholar 

  • Mañucat-Tan, N. B., Shen, L.-L., Bobrovskaya, L., Al-Hawwas, M., Zhou, F. H., Wang, Y.-J., & Zhou, X.-F. (2019). Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model. Aging, 11, 6762–6791.

    Article  Google Scholar 

  • Martinowich, K., Schloesser, R. J., Lu, Y., Jimenez, D. V., Paredes, D., Greene, J. S., Greig, N. H., Manji, H. K., & Lu, B. (2012). Roles of p75(NTR), long-term depression, and cholinergic transmission in anxiety and acute stress coping. Biological Psychiatry, 71, 75–83.

    Article  CAS  Google Scholar 

  • Meeker, R., & Williams, K. (2014). Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. Journal of Neuroimmune Pharmacology, 9, 615–628.

    Article  Google Scholar 

  • Morillo, S. M., Escoll, P., De La Hera, A., & Frade, J. M. (2010). Somatic tetraploidy in specific chick retinal ganglion cells induced by nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America, 107, 109–114.

    Article  CAS  Google Scholar 

  • Morillo, S. M., Abanto, E. P., Roman, M. J., & Frade, J. M. (2012). Nerve growth factor-induced cell cycle reentry in newborn neurons is triggered by p38MAPK-dependent E2F4 phosphorylation. Molecular and Cellular Biology, 32, 2722–2737.

    Article  CAS  Google Scholar 

  • Mufson, E. J., Counts, S. E., Ginsberg, S. D., Mahady, L., Perez, S. E., Massa, S. M., Longo, F. M., & Ikonomovic, M. D. (2019). Nerve growth factor pathobiology during the progression of Alzheimer’s disease. Frontiers in Neuroscience, 13, 533.

    Article  Google Scholar 

  • Murphy, M., Wilson, Y. M., Vargas, E., Munro, K. M., Smith, B., Huang, A., Li, Q. X., Xiao, J., Masters, C. L., Reid, C. A., & Barrett, G. L. (2015). Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease. Neurobiology of Aging, 36, 740–752.

    Article  CAS  Google Scholar 

  • Nguyen, T. V., Shen, L., Vander Griend, L., Quach, L. N., Belichenko, N. P., Saw, N., Yang, T., Shamloo, M., Wyss-Coray, T., Massa, S. M., & Longo, F. M. (2014). Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AbetaPP(L/S) transgenic mice. Journal of Alzheimer’s Disease, 42, 459–483.

    Article  CAS  Google Scholar 

  • Ovsepian, S. V., Antyborzec, I., O’leary, V. B., Zaborszky, L., Herms, J., & Oliver Dolly, J. (2014). Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Abeta) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons. Brain Structure & Function, 219, 1527–1541.

    Article  CAS  Google Scholar 

  • Pincheira, R., Baerwald, M., Dunbar, J. D., & Donner, D. B. (2009). Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth. The EMBO Journal, 28, 261–273.

    Article  CAS  Google Scholar 

  • Qian, L., Milne, M. R., Shepheard, S., Rogers, M. L., Medeiros, R., & Coulson, E. J. (2019). Removal of p75 neurotrophin receptor expression from cholinergic basal forebrain neurons reduces amyloid-beta plaque deposition and cognitive impairment in aged APP/PS1 mice. Molecular Neurobiology, 56, 4639–4652.

    Article  CAS  Google Scholar 

  • Riffault, B., Kourdougli, N., Dumon, C., Ferrand, N., Buhler, E., Schaller, F., Chambon, C., Rivera, C., Gaiarsa, J. L., & Porcher, C. (2016). Pro-brain-derived neurotrophic factor (proBDNF)-mediated p75NTR activation promotes depolarizing actions of GABA and increases susceptibility to epileptic seizures. Cerebral Cortex, 28, 510–527.

    Google Scholar 

  • Saadipour, K., Manucat-Tan, N. B., Lim, Y., Keating, D. J., Smith, K. S., Zhong, J. H., Liao, H., Bobrovskaya, L., Wang, Y. J., Chao, M. V., & Zhou, X. F. (2018). p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. Journal of Neurochemistry, 144, 302–317.

    Article  CAS  Google Scholar 

  • Shen, L. L., Manucat-Tan, N. B., Gao, S. H., Li, W. W., Zeng, F., Zhu, C., Wang, J., Bu, X. L., Liu, Y. H., Gao, C. Y., Xu, Z. Q., Bobrovskaya, L., Lei, P., Yu, J. T., Song, W., Zhou, H. D., Yao, X. Q., Zhou, X. F., & Wang, Y. J. (2018). The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau. Molecular Psychiatry, 23, 1813–1824.

    Article  CAS  Google Scholar 

  • Shen, L.-L., Li, W.-W., Xu, Y.-L., Gao, S.-H., Xu, M.-Y., Bu, X.-L., Liu, Y.-H., Wang, J., Zhu, J., Zeng, F., Yao, X.-Q., Gao, C.-Y., Xu, Z.-Q., Zhou, X.-F., & Wang, Y.-J. (2019). Neurotrophin receptor p75 mediates amyloid β-induced tau pathology. Neurobiology of Disease, 132, 104567.

    Article  CAS  Google Scholar 

  • Song, W., Volosin, M., Cragnolini, A. B., Hempstead, B. L., & Friedman, W. J. (2010). ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. The Journal of Neuroscience, 30, 15608–15615.

    Article  CAS  Google Scholar 

  • Spuch, C., & Carro, E. (2011). The p75 neurotrophin receptor localization in blood-CSF barrier: Expression in choroid plexus epithelium. BMC Neuroscience, 12, 39.

    Article  CAS  Google Scholar 

  • Tabaton, M., Zhu, X., Perry, G., Smith, M. A., & Giliberto, L. (2010). Signaling effect of amyloid-beta(42) on the processing of AbetaPP. Experimental Neurology, 221, 18–25.

    Article  CAS  Google Scholar 

  • Tiernan, C. T., Ginsberg, S. D., He, B., Ward, S. M., Guillozet-Bongaarts, A. L., Kanaan, N. M., Mufson, E. J., & Counts, S. E. (2018). Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer’s disease. Neurobiology of Disease, 117, 125–136.

    Article  CAS  Google Scholar 

  • Vicario, A., Kisiswa, L., Tann, J. Y., Kelly, C. E., & Ibanez, C. F. (2015). Neuron-type-specific signaling by the p75NTR death receptor is regulated by differential proteolytic cleavage. Journal of Cell Science, 128, 1507–1517.

    CAS  Google Scholar 

  • Wang, Y. J., Wang, X., Lu, J. J., Li, Q. X., Gao, C. Y., Liu, X. H., Sun, Y., Yang, M., Lim, Y., Evin, E., Zhong, J. H., Masters, C., & Zhou, X. F. (2011). p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. The Journal of Neuroscience, 31, 2292–2304. Epub ahead of print.

    Google Scholar 

  • Wang, Y.-R., Wang, J., Liu, Y.-H., Hu, G.-L., Gao, C.-Y., Wang, Y.-J., Zhou, X.-F., & 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. Journal of Alzheimer’s Disease, 63, 139–147.

    Article  CAS  Google Scholar 

  • Wong, L. W., Tann, J. Y., Ibanez, C. F., & Sajikumar, S. (2019). The p75 neurotrophin receptor is an essential mediator of impairments in hippocampal-dependent associative plasticity and memory induced by sleep deprivation. The Journal of Neuroscience, 39, 5452–5465.

    Article  CAS  Google Scholar 

  • Yang, T., Liu, H., Tran, K. C., Leng, A., Massa, S. M., & Longo, F. M. (2020a). Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice. Acta Neuropathologica Communications, 8, 156.

    Google Scholar 

  • Yang, T., Tran, K. C., Zeng, A. Y., Massa, S. M., & Longo, F. M. (2020b). Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies. Scientific Reports, 10, 20322.

    Google Scholar 

  • Yao, X. Q., Jiao, S. S., Saadipour, K., Zeng, F., Wang, Q. H., Zhu, C., Shen, L. L., Zeng, G. H., Liang, C. R., Wang, J., Liu, Y. H., Hou, H. Y., Xu, X., Su, Y. P., Fan, X. T., Xiao, H. L., Lue, L. F., Zeng, Y. Q., Giunta, B., Zhong, J. H., Walker, D. G., Zhou, H. D., Tan, J., Zhou, X. F., & Wang, Y. J. (2015). p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Molecular Psychiatry, 20, 1301–1310.

    Article  CAS  Google Scholar 

  • Zanin, J. P., Abercrombie, E., & Friedman, W. J. (2016). Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor. eLife, 5, e16654.

    Google Scholar 

  • Zanin, J. P., Verpeut, J. L., Li, Y., Shiflett, M. W., Wang, S. S. H., Santhakumar, V., & Friedman, W. J. (2019). The p75NTR influences cerebellar circuit development and adult behavior via regulation of cell cycle duration of granule cell progenitors. The Journal of Neuroscience, 39, 9119–9129.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Army 953 Hospital, Third Military Medical University, Shigatse, China

    Lin-Lin Shen

  2. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China

    Fan Zeng & Yan-Jiang Wang

  3. Departments of Cell Biology, Physiology & Neuroscience, and Psychiatry, Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, NY, USA

    Khalil Saadipour

  4. Division of Health Sciences, University of South Australia, Adelaide, SA, Australia

    Jian-Jun Lu & Xin-Fu Zhou

Authors
  1. Lin-Lin Shen
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  2. Fan Zeng
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  3. Khalil Saadipour
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  4. Jian-Jun Lu
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  5. Xin-Fu Zhou
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  6. Yan-Jiang Wang
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Corresponding authors

Correspondence to Xin-Fu Zhou or Yan-Jiang Wang .

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Editors and Affiliations

  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Shen, LL., Zeng, F., Saadipour, K., Lu, JJ., Zhou, XF., Wang, YJ. (2022). p75NTR: A Molecule with Multiple Functions in Amyloid-β Metabolism and Neurotoxicity. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_28

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