Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of Neuron Loss in Alzheimer’s Disease

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

One of the main elements in the pathogenesis of Alzheimer’s disease consists of larger decreases in the numbers of neurons in various parts of the brain than seen in normal ageing. The relevance of studying the pathogenesis of this process arises from the fact that neuron loss starts at the early, preclinical stage of Alzheimer’s disease, when amyloid plaques and neurofibrillary tangles (the main morphological signs of the disease) have still not formed; neuron loss correlates with the extent of clinical signs of the disease. Data have now accumulated on the likely pathogenetic mechanisms of neuron loss. The aim of the present literature review was to summarize these data.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. E. D. Bazhanova, V. N. Molodtsov, and K. I. Pavlov, “Changes in the expression of apoptosis-associated molecules in neurosecretory cells of the hypothalamus in mice during aging,” Morfologiya, 130, No. 6, 35–39 (2006).

    CAS  Google Scholar 

  2. Yu. B. Belousov, S. K. Zyryanov, D. Yu. Belousov, and A. S. Beketov, “Clinical-economical aspects of the treatment of Alzheimer’s disease in Russia,” Kachestv. Klin. Prakt., S1, 3–28 (2009).

  3. I. B. Besprozvannyi, “The calcium signaling system in neurodegeneration,” Acta Nature (Russian version), 2, No. 1, 80–88 (2010).

    Google Scholar 

  4. S. I. Gavrilov and Ya. B. Kalyn, “Socially mediated factors and the state of mental health in the elderly population,” Vestn. Ros. Akad. Med. Nauk., No. 9, 15–20 (2002).

  5. D. E. Korzhevskii, “Neurogenesis and neural stem cells,” Med. Akad. Zh., 10, No. 4, 175–182 (2010).

    Google Scholar 

  6. D. E. Korzhevskii, O. V. Kirik, and E. G. Gilerovich, “Postnatal neurogenesis: cell identification and terminology,” Morfologiya, 144, No. 4, 88–92 (2013).

    CAS  Google Scholar 

  7. V. N. Mukhin, “Pathogenetic mechanisms of dysfunction of the cholinergic system in Alzheimer’s disease,” Ros. Fiziol. Zh., 99, No. 7, 793–804 (2013).

    CAS  Google Scholar 

  8. E. A. Popugaeva, O. L. Vlasova, and I. B. Besprozvannyi, “The role of intracellular calcium in the development of the pathogenesis of Alzheimer’s disease,” Nauchno-Tekhn. Ved. St. Peterburg. Univ. Fiz. Mat. Nauki, 189, No. 1, 79–90 (2014).

    Google Scholar 

  9. J. B. Aimone, J. Wiles, and F. H. Gage, “Potential role for adult neurogenesis in the encoding of time in new memories,” Nature Neurosci., 9, No. 6, 723–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. A. D. Buttelfield, A. Castegna, C. M. Lauderback, and J. Drake, “Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death,” Neurobiol. Aging, 23, No. 5, 655–664 (2002).

    Article  Google Scholar 

  11. J. W. Allen, B. A. Eldadah, X. Huang, et al., “Multiple caspases are involved in β-amyloid-induced neuronal apoptosis,” J. Neurosci. Res., 65, No. 1, 45–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. B. B. Andersen, L. Korbo, and B. Pakkenberg, “A quantitative study of the human cerebellum with unbiased stereological techniques,” J. Comp. Neurol., 326, No. 4, 549–560 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. T. Arendt, V. Bigl, A. Arendt, and A. Tennstedt, “Loss of neurons in the nucleus basalis of Meynert in Alzheimer’ s disease, paralysis agitans and Korsakoff’s disease,” Acta Neuropathol., 61, No. 2, 101–108 (1983).

    Article  CAS  PubMed  Google Scholar 

  14. N. Arispe, H. B. Pollard, and E. Rojas, “β-Amyloid Ca2+-channel hypothesis for neuronal death in Alzheimer disease,” Mol. Cell. Biochem., 140, No. 2, 119–125 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. F. A. C. Azevedo, L. R. B. Carvalho, L. T. Grinberg, et al., “Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain,” J. Comp. Neurol., 513, No. 5, 532–541 (2009).

    Article  PubMed  Google Scholar 

  16. M. J. Bali, “Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia,” Acta Neuropathol., 37, No. 2, 111–118 (1977).

    Article  Google Scholar 

  17. M. F. Beal, “Mitochondria take center stage in aging and neurodegeneration,” Ann. Neurol., 58, No. 4, 495–505 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. O. Bergmann, J. Liebl, S. Bernard, et al., “The age of olfactory bulb neurons in Humans,” Neuron, 74, No. 4, 634–639 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. S. Bernales, M. A. Morales Soto, and E. McCullagh, “Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration,” Front. Aging Neurosci., 4, 5 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. K. Boekhoorn, M. Joels, and P. J. Lucassen, “Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus,” Neurobiol. Dis., 24, No. 1, 1–14 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. W. Bondareff, C. Q. Mountjoy, and M. Roth, “Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia,” Neurology, 32, No. 2, 164–168 (1982).

    Article  CAS  PubMed  Google Scholar 

  22. M. A. Bradley-Whitman and M. A. Lovell, “Biomarkers of lipid peroxidation in Alzheimer disease (AD), an update,” Arch. Toxicol., 89, No. 7, 1035–1044 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. D. E. Bredesen, R. V. Rao, and P. Mehlen, “Cell death in the nervous system,” Nature, 443, No. 7113, 796–802 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. A. Camins, M. Pallas, and J. S. Silvestre, “Apoptotic mechanisms involved in neurodegenerative diseases: Experimental and therapeutic approaches,” Methods Find. Exp. Clin. Pharmacol., 30, No. 1, 43 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. C. Caspersen, N. Wang, J. Yao, et al., “Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease,” FASEB J., 19, No. 14, 2040–2041 (2005).

    CAS  PubMed  Google Scholar 

  26. S. Chen, J. M. Wang, R. W. Irwin, et al., “Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer’s disease,” PLoS One, 6, No. 8, e24293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. T. T. Chuang, “Neurogenesis in mouse models of Alzheimer’s disease,” Biochem. Biophys. Acta Mol. Basis Dis., 1802, No. 10, 872–880 (2010).

    Article  CAS  Google Scholar 

  28. J. R. Cirrito, K. A. Yamada, M. B. Finn, et al., “Synaptic activity regulates interstitial β-amyloid-beta levels in vivo,” Neuron, 48, No. 6, 913–922 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. A. R. Cole, A. Knebel, N. A. Morrice, et al., “GSK-3 phosphorylation of the alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons,” J. Biol. Chem., 279, No. 48, 50 176–50 180 (2004).

    Article  CAS  Google Scholar 

  30. P. D. Coleman and D. G., Flood, “Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease,” Neurobiol. Aging, 8, No. 6, 521–545 (1987).

  31. C. M. Cooper-Kuhn, J. Winkler, and H. G. Kuhn, “Decreased neurogenesis after cholinergic forebrain lesion in the adult rat,” J. Neurosci. Res., 77, No. 2, 155–165 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. W. Deng, M. D. Saxe, I. S. Gallina, and F. H. Gage, “Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain,” J. Neurosci., 29, No. 43, 13532–13542 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. B. De Strooper, R. Vassar, and T. Golde, “The secretases: enzymes with therapeutic potential in Alzheimer disease,” Nat. Rev. Neurol., 6, No. 2, 99–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. K. T. Dineley, M. Westerman, D. Bui, et al., “β-Amyloid activates the mitogen-activated protein kinase cascade via hippocampal α7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer’s disease,” J. Neurosci., 21, No. 12, 4125–4133 (2001).

    CAS  PubMed  Google Scholar 

  35. C. Di Scala, J-D. Troadec, C. Lelievre, et al., “Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer β-amyloid peptide,” J. Neurochem., 128, No. 1, 186–195 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. A. Ernst, K. Alkass, S. Bernard, et al., “Neurogenesis in the Striatum of the adult human brain,” Cell, 156, No. 5, 1072–1083 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. S. M. Fayaz, V. S. Suvanish Kumar, and G. K. Rajanikant, “Necroptosis: Who knew there were so many interesting ways to die?” CNS Neurol. Disord. Drug Targets, 13, No. 1, 42–51 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. P. Fernández-Vizarra, A. P. Fernández, S. Castro-Blanco, et al., “Intra and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer’s disease,” Histol. Histopathol., 19, No. 3, 823–844 (2004).

    PubMed  Google Scholar 

  39. P. Ferreira, R. Villanueva, L. A. Cabon, et al., “The oxido-reductase activity of the apoptosis inducing factor: A promising pharmacological tool?” Curr. Pharm. Des., 19, No. 14, 2628–2636 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. A. M. Fjell and K. B. Walhovd, “Structural brain changes in aging: courses, causes and cognitive consequences,” Rev. Neurosci., 21, No. 3, 187–222 (2011).

    Google Scholar 

  41. Y. Fukata, T. J. Itoh, T. Kimura, et al., “CRMP-2 binds to tubulin heterodimers to promote microtubule assembly,” Nature Cell Biol., 4, No. 8, 583–591 (2002).

    CAS  PubMed  Google Scholar 

  42. J. J. Garrido, D. Simón, O. Varea, and F. Wandosell, “GSK3 alpha and GSK3 beta are necessary for axon formation,” FEBS Lett., 581, No. 8, 1579–1586 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. M. C. Gastard, J. C. Troncoso, and V. E. Koliatsos, “Caspase activation in the limbic cortex of subjects with early Alzheimer’s disease,” Ann. Neurol., 54, No. 3, 393–398 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. P. Giannakopoulos, F. R. Herrmann, T. Bussiere, et al., “Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease,” Neurology, 60, No. 9, 1495–1500 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. T. Gómez-Isla, J. L. Price, D. W. McKeel, Jr., et al., “Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease,” J. Neurosci., 16, No. 14, 4491–4500 (1996).

    PubMed  Google Scholar 

  46. C. Göritz and J. Frisén, “Neural stem cells and neurogenesis in the adult,” Cell Stem Cell, 10, No. 6, 657–659 (2012).

    Article  PubMed  CAS  Google Scholar 

  47. E. Gould, A. Beylin, P. Tanapat, et al., “Learning enhances adult neurogenesis in the hippocampal formation,” Nature Neurosci., 2, No. 3, 260–265 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. G. K. Gouras, J. Tsai, J. Naslund, et al., “Intraneuronal Af342 accumulation in human brain,” Am. J. Pathol., 156, No. 1, 15–20 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. E. Hangen, K. Blomgren, P. Bénit, et al., “Life with or without AIF,” Trends Biochem. Sci., 35, No. 5, 278–287 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. T. Harkany, I. Ábraham, W. Timmerman, et al., “β-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis,” Eur. J. Neurosci., 12, No. 8, 2735–2745 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. N. J. Haughey, A. Nath, S. L. Chan, et al., “Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease,” J. Neurochem., 83, No. 6, 1509–1524 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. C. M. Hernandez, and K. T. Dineley, “α7 Nicotinic acetylcholine receptors in Alzheimer’s disease: neuroprotective, neurotrophic or both?” Curr. Drug Targets, 13, No. 5, 613–622 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. J. J. M. Hoozemans, R. Veerhuis, E. S. V. Haastert, et al., “The unfolded protein response is activated in Alzheimer’ s disease,” Acta Neuropathol., 110, No. 2, 165–172 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. J. Hroudova, N. Singh, and Z. Figar, “Mitochondrial dysfunctions in neurodegenerative diseases: Relevance to Alzheimer’s disease,” BioMed Res. Int., 2014, e175062 (2014).

  55. E.-M. Hur and F.-Q. Zhou, “GSK3 signalling in neural development,” Nat. Rev. Neurosci., 11, No. 8, 539–551 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. B. T. Hynan, “Caspase activation without apoptosis: insight into Aβ initiation of neurodegeneration,” Nat. Neurosci., 14, No. 1, 5–6 (2011).

    Article  CAS  Google Scholar 

  57. R. W. Irwin, J. M. Wang, S. Chen, and R. D. Brinton, “Neuroregenerative mechanisms of allopregnanolone in Alzheimer’s disease,” Front. Endocrinol. (Lausanne), 12, No. 2, 117 (2012).

    Google Scholar 

  58. K. M. Jacobs, S. R. Bhave, D. J. Ferraro, et al., “GSK-3β, a bifunctional role in cell death pathways,” Int. J. Cell Biol., 2012, 2012, e930710 (2012).

  59. T. Jaworski, S. Kügler, and F. Van Leuven, “Modeling of tau-mediated synaptic and neuronal degeneration in Alzheimer’s disease,” Int. J. Alzheimer’s Dis., 2010: 1–10 (2010).

    Article  Google Scholar 

  60. H. Jiang, W. Guo, X. Liang, and Y. Rao, “Both the establishment and the maintenance of neuronal polarity require active mechanisms: Critical roles of GSK-3β and its upstream regulators,” Cell, 120, No. 1, 123–135 (2005).

    CAS  PubMed  Google Scholar 

  61. K. Jin, A. L. Peel, X. O. Mao, et al., “Increased hippocampal neurogenesis in Alzheimer’s disease,” Proc. Natl. Acad. Sci. USA, 101, No. 1, 343–347 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. G. V. Johnson and W. H. Stoothoff, “Tau phosphorylation in neuronal cell function and dysfunction,” J. Cell Sci., 117, No. 24, 5721–5729 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. F. Kamenetz, T. Tomita, H. Hsieh, et al., “APP processing and synaptic function,” Neuron, 37, No. 6, 925–937 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. M. Kelliher, J. Fastbom, R. F. Cowburn, et al., “Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer’s disease neurofibrillary and β-amyloid pathologies,” Neuroscience, 92, No. 2, 499–513 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. G. Kempermann and F. H., Gage, “New nerve cells for the adult brain,” Sci. Am., 280, No. 5, 48–53 (1999).

  66. S. Knafo, “Amygdala in Alzheimer’s disease,” in: The Amygdala – a Discrete Multitasking Manager, B. Ferry (ed.), InTech (2012), pp. 375–384.

  67. R. Knoth, L. Singec, M. Ditter, et al., “Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years,” PLoS One, 5 (1), e8809 (2010).

  68. A. J. Kole, R. P. Annis, and M. Deshmukh, “Mature neurons: equipped for survival,” Cell Death Dis., 4 No. 6, e689 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. U. Konietzko, “AICD nuclear signaling and its possible contribution to Alzheimer’s diseasem” Curr. Alzheimer Res., 9, No. 2, 200–216 (2012).

    Article  CAS  Google Scholar 

  70. A. Kremer, J. V. Louis, T. Jaworski, and F. Van Leuven, “GSK3 and Alzheimer’s disease: facts and fiction,” Front. Mol. Neurosci., No. 4 (2011).

  71. P. Kurup, Y. Zhang, J. Xu, et al., “Aβ-Mediated NMDA receptor endocytosis in Alzheimer’s disease involves ubiquitination of the tyrosine phosphatase STEP61,” J. Neurosci., 30, No. 17, 5948–5957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. J.-H. Lee, Y.-H. Cheon, R.-S. Woo, et al., “Evidence of early involvement of apoptosis inducing factor-induced neuronal death in Alzheimer brain,” Anatomy Cell Biol., 45, No. 1, 26 (2012).

    Article  Google Scholar 

  73. M. A. Leissring, M. P. Murphy, T. R. Mead, et al., “A physiologic signaling role for the y-secretase-derived intracellular fragment of APP,” Proc. Natl. Acad. Sci. USA, 99, No. 7, 4697–4702 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. K. Leroy, Z. Yilmaz, and J.-P. Brion, “Increased level of active GSK-3β in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration,” Neuropathol. Appl. Neurobiol., 33, No. 1, 43–55 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. B. Li, H. Yamamori, Y. Tatebayashi, et al., “Failure of neuronal maturation in Alzheimer disease dentate gyrus,” J. Neuropathol. Exp. Neurol., 67, No. 1, 78–84 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. L. Lossi and A. Merighi, “In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS,” Progr. Neurobiol., 69, No. 5, 287–312 (2003).

    Article  CAS  Google Scholar 

  77. J. P. Magnusson, C. Göritz, J. Tatarishvili, et al., “A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse,” Science, 346, No. 6206, 237–241 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. J. Magrané, K. M. Rosen, R. C. Smith, et al., “Intraneuronal β-amyloid expression downregulates the Akt survival pathway and blunts the stress response,” J. Neurosci., 25, No. 47, 10 960–10 969 (2005).

    Article  CAS  Google Scholar 

  79. M. Manczak, T. S. Anekonda, E. Henson, et al., “Mitochondria are a direct site of Af3 accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression,” Hum. Mol. Genet., 15, No. 9, 1437–1449 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. C. E. Marx, W. T. Trost, L. J. Shampine, et al., “The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease,” Biol. Psychiatry, 60, No. 12, 1287–1294 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. T. Matsui, K. Ramasamy, M. Ingelsson, et al., “Coordinated expression of caspase 8, 3 and 7 mRNA in temporal cortex of Alzheimer disease: Relationship to formic acid extractable Aβ42 levels,” J. Neuropathol. Exp. Neurol., 65, No. 5, 508–515 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. M. P. Mattson, “Pathways towards and away from Alzheimer’s disease,” Nature, 430, No. 7000, 631–639 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. M. P. Mattson, B. Cheng, D. Davis, et al., “Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity,” J. Neurosci., 12, No. 2, 376–389 (1992).

    CAS  PubMed  Google Scholar 

  84. T. K. Mehta, J. J. Dougherty, J. Wu, et al., “Defining pre-synaptic nicotinic receptors regulated by beta amyloid in mouse cortex and hippocampus with receptor null mutants,” J. Neurochem., 109, No. 5, 1452–1458 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. C. C. Meltzer, G. Smith, S. T. DeKosky, et al., “Serotonin in aging, late-life depression, and Alzheimer’s disease: The emerging role of functional imaging,” Neuropsychopharmacology, 18, No. 6, 407–430 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. A. K. H. Miller, R. L. Alston, C. Q. Mountjoy, and J. A. N. Corsellis, “Automated differential cell counting on a sector of the normal human hippocampus: The influence of age,” Neuropathol. Appl. Neurobiol., 10, No. 2, 123–141 (1984).

    Article  CAS  PubMed  Google Scholar 

  87. A. Mohamed and F. Posse de Chaves, “Aβ internalization by neurons and glia,” Int. J. Alzheimer’s Disease, 2011, 1–17 (2011).

    Article  CAS  Google Scholar 

  88. J. H. Morrison and P. R. Hof, “Life and death of neurons in the aging brain,” Science, 278, No. 5337, 412–419 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. T. Müller, H. E. Meyer, R. Egensperger, and K. Marcus, “The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics – Relevance for Alzheimer’s disease,” Progr. Neurobiol., 85, No. 4, 393–406 (2008).

    Article  CAS  Google Scholar 

  90. T. Nakagawa, H. Zhu, N. Morishima, et al., “Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β,” Nature, 403, No. 6765, 98–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. L. Lossi and A. Merighi (eds.), Neuronal Cell Death: An Overview of Its Different Forms in Central and Peripheral Neurons, Springer, New York (2015).

    Google Scholar 

  92. R. A. Nixon and D.-S. Yang, “Autophagy failure in Alzheimer’s disease-locating the primary defect,” Neurobiol. Dis., 43, No. 1, 38–45 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. S. C. Noctor, V. Martinez-Cerdeño, and A. R. Kriegstein, “Contribution of intermediate pronitor cells to cortical histogenesis,” Arch. Neurol., 64, No. 5, 639–642 (2007).

    Article  PubMed  Google Scholar 

  94. R. J. O’Brien and P. C. Wong, “Amyloid precursor protein processing and Alzheimer’s disease,” Annu. Rev. Neurosci., 34, 185–204 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. B. Pakkenberg and H. J. G. Gundersen, “Neocortical neuron number in humans: Effect of sex and age,” J. Comp. Neurol., 384, No. 2, 312–320 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. B. Pakkenberg, D. Pelvig, L. Marner, et al., “Aging and the human neocortex,” Exp. Gerontology, 38, No. 1–2, 95–99 (2003).

    Article  Google Scholar 

  97. M. S. Parihar and G. J. Brewer, “Amyloid beta as a modulator of synaptic plasticity,” J. Alzheimers Dis., 22, No. 3, 741–763 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. J. J. Pei, E. Braak, H. Braak, et al., “Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes,” J. Neuropathol. Exp. Neurol., 58, No. 9, 1010–1019 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. D. P. Pelvig, H. Pakkenberg, A. K. Stark, and B. Pakkenberg, “Neocortical glial cell numbers in human brains,” Neurobiol. Aging, 29, No. 11, 1754–1762 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. P. N. Pompl, S. Yemul, Z. Xiang, et al., “Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease,” Arch. Neurol., 60, No. 3, 369–376 (2003).

    Article  PubMed  Google Scholar 

  101. J. L. Price, A. I. Ko, M. J. Wade, et al., “Neuron number in the entorhinal cortex and ca1 in preclinical Alzheimer disease,” Arch. Neurol., 58, No. 9, 1395–1402 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. A. Quist, I. Doudevski, H. Lin, et al., “Amyloid ion channels: A common structural link for protein-misfolding disease,” Proc. Natl. Acad. Sci. USA, 102, No. 30, 10,427–10,432 (2005).

    Article  CAS  Google Scholar 

  103. C. A. Raji, O. L. Lopez, L. H. Kuller, et al., “Age, Alzheimer disease, and brain structure,” Neurology, 73, No. 22, 1899–1905 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. C. G. Rasool, C. N. Svendsen, and D. J. Selkoe, “Neurofibrillary degeneration of cholinergie and noncholinergic neurons of the basal forebrain in Alzheimer’s disease,” Ann. Neurol., 20, No. 4, 482–488 (1986).

    Article  CAS  PubMed  Google Scholar 

  105. J. J. Rodriguez and A. Verkhratsky, “Neurogenesis in Alzheimer’s disease,” J. Anat., 219, No. 1, 78–89 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  106. L. Saavedra, A. Mohamed, V. Ma, et al., “Internalization of β-amyloid peptide by primary neurons in the absence of apolipoprotein E,” J. Biol. Chem., 282, No. 49, 35 722–35 732 (2007).

    Article  CAS  Google Scholar 

  107. N. Sanai, T. Nguyen, R. A. Ihrie, et al., “Corridors of migrating neurons in the human brain and their decline during infancy,” Nature, 478, No. 7369, 382–386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. E. A. Schon and E. Area-Gomez, “Mitochondria-associated ER membranes in Alzheimer disease,” Mol. Cell. Neurosci., 55, 26–36 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. I. F. Sevrioukova, “Apoptosis-inducing factor: Structure, function, and redox regulation,” Antioxid. Redox Signal., 14, No. 12, 2545–2579 (2010).

    Article  CAS  Google Scholar 

  110. S. Shimohama, H. Tanino, and S. Fujimoto, “Changes in caspase expression in Alzheimer’s disease: comparison with development and aging,” Biochem. Biophys. Res. Commun., 256, No. 2, 381–384 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. S.-H. Shi, T. Cheng, L. Jan, and Y.-N. Jan, “APC and GSK-3β are involved in mPar3 Targeting to the nascent axon and establishment of neuronal polarity,” Curr. Biol., 14, No. 22, 2025–2032 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. T. J. Shors, D. A. Townsend, M. Zhao, et al., “Neurogenesis may relate to some but not an types of hippocampal-dependent learning,” Hippocampus, 12, No. 5, 578– 584 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  113. G. Šimić and N. Bogdanović, “Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease,” J. Comp. Neurol., 379, No. 4, 482–494 (1997).

    Article  PubMed  Google Scholar 

  114. G. Smale, N. R. Nichols, D. R. Brady, et al., “Evidence for apoptotic cell death in Alzheimer’s disease,” Exp. Neurology, 133, No. 2, 225–230 (1995).

    Article  CAS  Google Scholar 

  115. K. J. Smillie and M. A. Cousin, “The role of GSK3 in presynaptic function,” Int. J. Alzheimer Dis. (2011), doi: 10.4061/2011/263673, www.hindawi.com/journals/journals/ijad/2011/263673, publ. March 14, 2011, acces. May 27, 2013.

  116. S. Snigdha, E. D. Smith, G. A. Prieto, and C. W. Cotman, “Caspase-3 activation as a bifurcation point between plasticity and cell death,” Neurosci. Bull., 28, No. 1, 14–24 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. K. L. Spalding, O. Bergmann, K. Alkass, et al., “Dynamics of hippocampal neurogenesis in adult humans,” Cell, 153, No. 6, 1219–1227 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. W. Sun, A. Winseck, S. Vinsant, et al., “Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene bax,” J. Neurosci., 24, No. 49, 11205–11213 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. C. Supnet and I. Bezprozvanny, “The dysregulation of intracellular calcium in Alzheimer disease,” Cell Calcium, 47, No. 2, 183–189 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. H. J. Ter Laak, K. Renkawek, and F. P. van Workum, “The olfactory bulb in Alzheimer disease: a morphologic study of neuron loss, tangles, and senile plaques in relation to olfaction,” Alzheimer Dis. Assoc. Disord., 8, No. 1, 38–48 (1994).

    Article  CAS  PubMed  Google Scholar 

  121. R. D. Terry, R. DeTeresa, and L. A. Hansen, “Neocortical cell counts in normal human adult aging,” Ann. Neurol., 21, No. 6, 530–539 (1987).

    Article  CAS  PubMed  Google Scholar 

  122. G. Tesco, Y. H. Koh, E. L. Kang, et al., “Depletion of GGA3 stabilizes BACE and enhances β-secretase activity,” Neuron, 54, No. 5, 721–737 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. C. M. Troy, S. A. Rabacchi, W. J. Friedman, et al., “Caspase-2 mediates neuronal cell death induced by β-amyloid,” J. Neurosci., 20, No. 4, 1386–1392 (2000).

    CAS  PubMed  Google Scholar 

  124. T. H. L. G. Vereecken, O. J. M. Vogels, and R. Nieuwenhuys, “Neuron loss and shrinkage in the amygdala in Alzheimer’ s disease,” Neurobiol. Aging, 15, No. 1, 45–54 (1994).

    Article  CAS  PubMed  Google Scholar 

  125. B. Vincent and F. Checler, “α-Secretase in Alzheimers disease and beyond: mechanistic, regulation and function in the shedding of membrane proteins,” Curr. Alzheimer Res., 9, No. 2, 140–156 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. J. M. Wang, P. B. Johnston, B. G. Bail, and R. D. Brinton, “The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression,” J. Neurosci., 25, No. 19, 4706–4718 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. J. M. Wang, C. Singh, L. Liu, et al., “Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer’s disease,” Proc. Natl. Acad. Sci. USA, 107, No. 14, 6498–6503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. D. Weinshenker, “Functional consequences of locus coeruleus degeneration in Alzheimer’s disease,” Curr. Alzheimer Res., 5, No. 3, 342–345 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. W. Wei, L. N. Nguyen, H. W. Kessels, et al., “Amyloid beta from axons and dendrites reduces local spine number and plasticity,” Nature Neurosci., 13, No. 2, 190–196 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. M. J. Wes and H. J. G. Gundersen, “Unbiased stereological estimation of the number of neurons in the human hippocampus,” J. Comp. Neurol., 296, No. 1, 1–22 (1990).

    Article  Google Scholar 

  131. P. J. Whitehouse, D. L. Price, A. W. Clark, et al., “Alzheimer disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis,” Ann. Neurol., 10, No. 2, 122–126 (1981).

    Article  CAS  PubMed  Google Scholar 

  132. P. J. Whitehouse, D. L. Price, R. G. Struble, et al., “Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain,” Science, 215, 1237–1239 (1982).

    Article  CAS  PubMed  Google Scholar 

  133. R. W. Williams and K. Herrup, “The control of neuron number,” Annu. Rev. Neurosci., 11, No. 1, 423–453 (1988).

    Article  CAS  PubMed  Google Scholar 

  134. L. Wiskott, M. J. Rasch, and G. Kempermann, “A functional hypothesis for adult hippocampal neurogenesis: Avoidance of catastrophic interference in the dentate gyrus,” Hippocampus, 16, No. 3, 329–343 (2006).

    Article  PubMed  Google Scholar 

  135. T. Yamatsuji, T. Matsui, T. Okamoto, et al., “G Protein-mediated neuronal DNA fragmentation induced by familial Alzheimer’ s disease-associated mutants of APP,” Science, 272, No. 5266, 1349–1352 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. T. Yoshimura, Y. Kawano, N. Arimura, et al., “GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity,” Cell, 120, No. 1, 137–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. C. Zarow, S. A. Lyness, J. A. Mortimer, and H. C. Chui, “Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases,” Arch. Neurol., 60, No. 3, 337–341 (2003).

    Article  PubMed  Google Scholar 

  138. L. Zhang, G. Kokkonen, and G. S. Roth, “Identification of neuronal programmed cell death in situ in the striatum of normal adult rat brain and its relationship to neuronal death during aging,” Brain Res., 677, No. 1, 177–179 (1995).

    Article  CAS  PubMed  Google Scholar 

  139. Y. Zhang, “Caspases in Alzheimer’s disease,” in: Neurodegenerative Diseases, U. Kishore (ed.), InTech (2013), pp. 125–150 (2013).

  140. X. Zhu, G. Perry, M. A. Smith, and X. Wang, “Abnormal mitochondrial dynamics in the Pathogenesis of Alzheimer’s disease,” J. Alzheimers Dis., 33, Suppl. 1, S253–S262 (2013).

    PubMed  PubMed Central  Google Scholar 

  141. X. Zhu, A. K. Raina, G. Perry, and M. A. Smith, “Apoptosis in Alzheimer disease: A mathematical improbability,” Curr. Alzheimer Res., 3, No. 4, 393–396 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. I. Ziabreva, E. Perry, R. Perry, et al., “Altered neurogenesis in Alzheimer’s disease,” J. Psychosom. Res., 61, No. 3, 311–316 (2006).

    Article  PubMed  Google Scholar 

  143. J. Zumbrunn, K. Kinoshita, A. Hyman, and I. S. Näthke, “Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation,” Curr. Biol., 11, No. 1, 44–49 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Physiology Department, Institute of Experimental Medicine, St. Petersburg, Russia

    V. N. Mukhin, K. I. Pavlov & V. M. Klimenko

Authors
  1. V. N. Mukhin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. I. Pavlov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. M. Klimenko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. N. Mukhin.

Additional information

Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 102, No. 2, pp. 113–129, February, 2016.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mukhin, V.N., Pavlov, K.I. & Klimenko, V.M. Mechanisms of Neuron Loss in Alzheimer’s Disease. Neurosci Behav Physi 47, 508–516 (2017). https://doi.org/10.1007/s11055-017-0427-x

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11055-017-0427-x

Keywords

Search

Navigation