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  • Review Article
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Calcium dyshomeostasis and intracellular signalling in alzheimer's disease

Nature Reviews Neuroscience volume 3, pages 862–872 (2002)Cite this article

Key Points

  • Alzheimer's disease is the leading cause of dementia, afflicting about 5% of the population over the age of 65, and 33–50% of those over 80. At present, there is no cure for this insidious disorder. Given that life expectancy in many populations is being extended, Alzheimer's disease will remain a huge clinical and economic burden for many societies.

  • A small percentage of cases of Alzheimer's disease are inherited in an autosomal-dominant fashion. At the neuropathological level, the familial and the more common sporadic cases are virtually indistinguishable. The age of onset is the main distinguishing feature between the two; in familial Alzheimer's disease, onset is generally earlier than the seventh decade.

  • Most familial cases result from missense mutations in the presenilin 1 (PS1) and PS2 genes, which lead to increased formation of the highly amyloidogenic amyloid-β peptide Aβ1–42. There is compelling evidence that presenilin might be the catalytic subunit of the γ-secretase complex, which is crucial for the formation of Aβ, although this is not universally accepted.

  • Disruption of calcium homeostasis is another feature that is always associated with clinical mutations in the presenilin genes. Mutations of both PS1 and PS2 disrupt the phosphoinositide signalling cascade, indicating that the destabilization of calcium homeostasis is a pathogenic pathway that is common to both PS1 and PS2.

  • An elevation of calcium-store content in the endoplasmic reticulum seems to be one mechanism by which presenilin mutations disrupt intracellular calcium signalling. In addition, capacitive calcium entry, which is a process for replenishing depleted calcium stores in the endoplasmic reticulum, is attenuated by presenilin mutations.

  • Some of the presenilin-dependent effects on calcium signalling are mediated by a γ-secretase-derived product. The amyloid precursor protein (APP) intracellular domain (AICD) regulates phosphoinositide-mediated calcium signalling through a γ-secretase-dependent signalling pathway. The intramembraneous proteolysis of APP has a signalling function that is analogous to that of Notch.

  • Calcium dysregulation is a crucial and proximal component of the pathogenesis of Alzheimer's disease, and is capable of eliciting the characteristic lesions of this disorder, including increased Aβ formation, the hyperphosphorylation of TAU and neuronal cell death.

Abstract

Calcium modulates many neural processes, including synaptic plasticity and apoptosis. Dysregulation of intracellular calcium signalling has been implicated in the pathogenesis of Alzheimer's disease. Increased intracellular calcium elicits the characteristic lesions of this disorder, including the accumulation of amyloid-β, the hyperphosphorylation of TAU and neuronal death. Conversely, neurodegeneration that is induced by amyloid-β or TAU is probably mediated by changes in calcium homeostasis. Disruption of calcium regulation in the endoplasmic reticulum mediates the most significant signal-transduction cascades that are associated with Alzheimer's disease. Moreover, mutations that cause familial Alzheimer's disease have been linked to intracellular calcium signalling pathways. Destabilization of calcium signalling seems to be central to the pathogenesis of Alzheimer's disease, and targeting this process might be therapeutically beneficial.

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Figure 1: Blips, puffs and waves.
Figure 2: Calcium release is potentiated by PS1 mutations.
Figure 3: Calcium homeostasis and Alzheimer's disease neuropathology.

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References

  1. Sisodia, S. S. & St George-Hyslop, P. H. γ-Secretase, Notch, Aβ and Alzheimer's disease: where do the presenilins fit in? Nature Rev. Neurosci. 3, 281–290 (2002).

    Article  CAS  Google Scholar 

  2. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Khachaturian, Z. S. Calcium, membranes, aging, and Alzheimer's disease. Introduction and overview. Ann. NY Acad. Sci. 568, 1–4 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Mattson, M. P. et al. Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 23, 222–229 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Etcheberrigaray, R. et al. Calcium responses in fibroblasts from asymptomatic members of Alzheimer's disease families. Neurobiol. Dis. 5, 37–45 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Larson, J., Lynch, G., Games, D. & Seubert, P. Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. Brain Res. 840, 23–35 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Guo, Q. et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nature Med. 5, 101–106 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Leissring, M. A. et al. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793–798 (2000).This was the first report to show that CCE is altered by mutant PS1, and implicates enhanced ER stores in the process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mattson, M. P. et al. β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mattson, M. P., Tomaselli, K. J. & Rydel, R. E. Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF. Brain Res. 621, 35–49 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Yoo, A. S. et al. Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561–572 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Chui, D. H. et al. Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nature Med. 5, 560–564 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Leissring, M. A. et al. A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP. Proc. Natl Acad. Sci. USA 99, 4697–4702 (2002).This paper describes a novel signalling role for AICD in regulating phosphoinositide calcium signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mattson, M. P., Lovell, M. A., Ehmann, W. D. & Markesbery, W. R. Comparison of the effects of elevated intracellular aluminum and calcium levels on neuronal survival and tau immunoreactivity. Brain Res. 602, 21–31 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Mattson, M. P. Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron 4, 105–117 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. Zheng, H. et al. Mice deficient for the amyloid precursor protein gene. Ann. NY Acad. Sci. 777, 421–426 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Heber, S. et al. Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 20, 7951–7963 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. von Koch, C. S. et al. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol. Aging 18, 661–669 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Kamal, A., Stokin, G. B., Yang, Z., Xia, C. H. & Goldstein, L. S. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28, 449–459 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A. & Goldstein, L. S. Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP. Nature 414, 643–648 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Nishimoto, I. et al. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein Go . Nature 362, 75–79 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Okamoto, T. et al. Intrinsic signaling function of APP as a novel target of three V642 mutations linked to familial Alzheimer's disease. EMBO J. 15, 3769–3777 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mbebi, C. et al. Amyloid precursor protein family-induced neuronal death is mediated by impairment of the neuroprotective calcium/calmodulin protein kinase IV-dependent signaling pathway. J. Biol. Chem. 277, 20979–20990 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Le, Y. et al. Amyloid β42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J. Neurosci. 21, RC123 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cao, X. & Sudhof, T. C. A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115–120 (2001).Reference 25 shows that the AICD fragment can form a transcriptionally active complex.

    Article  CAS  PubMed  Google Scholar 

  26. Goodman, Y. & Mattson, M. P. Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp. Neurol. 128, 1–12 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Mattson, M. P. et al. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10, 243–254 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Mattson, M. P. Secreted forms of β-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons. J. Neurobiol. 25, 439–450 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Koizumi, S. et al. The effect of a secreted form of β-amyloid-precursor protein on intracellular Ca2+ increase in rat cultured hippocampal neurones. Br. J. Pharmacol. 123, 1483–1489 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Barger, S. W., Fiscus, R. R., Ruth, P., Hofmann, F. & Mattson, M. P. Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of β-amyloid precursor. J. Neurochem. 64, 2087–2096 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Li, W. Y. et al. Suppression of an amyloid β peptide-mediated calcium channel response by a secreted β-amyloid precursor protein. Neuroscience 95, 1–4 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Guo, Q., Robinson, N. & Mattson, M. P. Secreted β-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis. J. Biol. Chem. 273, 12341–12351 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Meziane, H. et al. Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice. Proc. Natl Acad. Sci. USA 95, 12683–12688 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mattson, M. P. Calcium and neuronal injury in Alzheimer's disease. Contributions of β-amyloid precursor protein mismetabolism, free radicals, and metabolic compromise. Ann. NY Acad. Sci. 747, 50–76 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Nixon, R. A. et al. Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease. Ann. NY Acad. Sci. 747, 77–91 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Mattson, M. P., Engle, M. G. & Rychlik, B. Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons. Mol. Chem. Neuropathol. 15, 117–142 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Mattson, M. P., Barger, S. W., Begley, J. G. & Mark, R. J. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods Cell Biol. 46, 187–216 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Mattson, M. P. Free radicals and disruption of neuronal ion homeostasis in AD: a role for amyloid β-peptide? Neurobiol. Aging 16, 679–682 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Gibson, G. E. et al. Abnormalities in Alzheimer's disease fibroblasts bearing the APP670/671 mutation. Neurobiol. Aging 18, 573–580 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Kagan, B. L., Hirakura, Y., Azimov, R., Azimova, R. & Lin, M. C. The channel hypothesis of Alzheimer's disease: current status. Peptides 23, 1311–1315 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Arispe, N., Rojas, E. & Pollard, H. B. Alzheimer disease amyloid β protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc. Natl Acad. Sci. USA 90, 567–571 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Arispe, N., Pollard, H. B. & Rojas, E. Giant multilevel cation channels formed by Alzheimer disease amyloid β-protein [AβP-(1–40)] in bilayer membranes. Proc. Natl Acad. Sci. USA 90, 10573–10577 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Arispe, N., Pollard, H. B. & Rojas, E. The ability of amyloid β-protein [AβP (1–40)] to form Ca2+ channels provides a mechanism for neuronal death in Alzheimer's disease. Ann. NY Acad. Sci. 747, 256–266 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Arispe, N., Pollard, H. B. & Rojas, E. β-Amyloid Ca2+-channel hypothesis for neuronal death in Alzheimer disease. Mol. Cell. Biochem. 140, 119–125 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Bhatia, R., Lin, H. & Lal, R. Fresh and globular amyloid β protein (1–42) induces rapid cellular degeneration: evidence for AβP channel-mediated cellular toxicity. FASEB J. 14, 1233–1243 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Kawahara, M. & Kuroda, Y. Molecular mechanism of neurodegeneration induced by Alzheimer's β-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res. Bull. 53, 389–397 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Lin, M. C., Mirzabekov, T. & Kagan, B. L. Channel formation by a neurotoxic prion protein fragment. J. Biol. Chem. 272, 44–47 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Mirzabekov, T. A., Lin, M. C. & Kagan, B. L. Pore formation by the cytotoxic islet amyloid peptide amylin. J. Biol. Chem. 271, 1988–1992 (1996).References 40–48 describe the potential of Aβ to form calcium-permeable ion pores.

    Article  CAS  PubMed  Google Scholar 

  49. Kawahara, M., Kuroda, Y., Arispe, N. & Rojas, E. Alzheimer's β-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. J. Biol. Chem. 275, 14077–14083 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Hensley, K. et al. A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 3270–3274 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mark, R. J., Hensley, K., Butterfield, D. A. & Mattson, M. P. Amyloid β-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J. Neurosci. 15, 6239–6249 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Goodman, Y., Bruce, A. J., Cheng, B. & Mattson, M. P. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J. Neurochem. 66, 1836–1844 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Keller, J. N., Germeyer, A., Begley, J. G. & Mattson, M. P. 17β-Estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid β-peptide and iron. J. Neurosci. Res. 50, 522–530 (1997).References 50–53 show a mechanistic link between oxidative stress and calcium dyshomeostasis.

    Article  CAS  PubMed  Google Scholar 

  54. Querfurth, H. W. & Selkoe, D. J. Calcium ionophore increases amyloid β peptide production by cultured cells. Biochemistry 33, 4550–4561 (1994).Reference 54 shows that Aβ formation can be modulated by evoking calcium increases.

    Article  CAS  PubMed  Google Scholar 

  55. Querfurth, H. W., Jiang, J., Geiger, J. D. & Selkoe, D. J. Caffeine stimulates amyloid β-peptide release from β-amyloid precursor protein-transfected HEK293 cells. J. Neurochem. 69, 1580–1591 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Buxbaum, J. D., Ruefli, A. A., Parker, C. A., Cypess, A. M. & Greengard, P. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc. Natl Acad. Sci. USA 91, 4489–4493 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Akbari, Y. et al. Modulation of β-amyloid production through calcium signaling pathways. Soc. Neurosci. Abstr. 28 (in the press).

  58. Cook, D. G. et al. Alzheimer's Aβ1–42 is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nature Med. 3, 1021–1023 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Selkoe, D. J. Presenilin, Notch, and the genesis and treatment of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 11039–11041 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. De Strooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Ni, C. Y., Murphy, M. P., Golde, T. E. & Carpenter, G. γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179–2181 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Lee, H. J. et al. Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem. 277, 6318–6323 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Marambaud, P. et al. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 1948–1956 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864–870 (1996).

    Article  CAS  PubMed  Google Scholar 

  66. Li, Y. M. et al. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Wolfe, M. S. & Selkoe, D. J. Intramembrane proteases — mixing oil and water. Science 296, 2156–2157 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Wolfe, M. S. Presenilin and γ-secretase: structure meets function. J. Neurochem. 76, 1615–1620 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Weihofen, A., Binns, K., Lemberg, M. K., Ashman, K. & Martoglio, B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215–22218 (2002).Reference 66–70 provide the strongest argument in support of presenilin as the catalytic subunit of γ-secretase.

    Article  CAS  PubMed  Google Scholar 

  71. Wahrle, S. et al. Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 9, 11–23 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Francis, R. et al. aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev. Cell 3, 85–97 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Kopan, R. & Goate, A. Aph-2/Nicastrin: an essential component of γ-secretase and regulator of Notch signaling and Presenilin localization. Neuron 33, 321–324 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Wilson, C. A., Doms, R. W., Zheng, H. & Lee, V. M. Presenilins are not required for Aβ42 production in the early secretory pathway. Nature Neurosci. 5, 849–855 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Nakajima, M., Miura, M., Aosaki, T. & Shirasawa, T. Deficiency of presenilin-1 increases calcium-dependent vulnerability of neurons to oxidative stress in vitro. J. Neurochem. 78, 807–814 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Ito, E. et al. Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 534–538 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Leissring, M. A., Paul, B. A., Parker, I., Cotman, C. W. & LaFerla, F. M. Alzheimer's presenilin-1 mutation potentiates inositol 1,4,5-trisphosphate-mediated calcium signaling in Xenopus oocytes. J. Neurochem. 72, 1061–1068 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Smith, I. F. et al. Ca2+ stores and capacitative Ca2+ entry in human neuroblastoma (SH-SY5Y) cells expressing a familial Alzheimer's disease presenilin-1 mutation. Brain Res. (in the press).

  80. Raymond, C. R. & Redman, S. J. Different calcium sources are narrowly tuned to the induction of different forms of LTP. J. Neurophysiol. 88, 249–255 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Parent, A., Linden, D. J., Sisodia, S. S. & Borchelt, D. R. Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1. Neurobiol. Dis. 6, 56–62 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Zaman, S. H. et al. Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine. Neurobiol. Dis. 7, 54–63 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Barrow, P. A. et al. Functional phenotype in transgenic mice expressing mutant human presenilin-1. Neurobiol. Dis. 7, 119–126 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Chan, S. L., Mayne, M., Holden, C. P., Geiger, J. D. & Mattson, M. P. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J. Biol. Chem. 275, 18195–18200 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Cedazo-Minguez, A., Popescu, B. O., Ankarcrona, M., Nishimura, T. & Cowburn, R. F. The presenilin 1 ΔE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations. J. Biol. Chem. 277, 36646–36655 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Guo, Q., Christakos, S., Robinson, N. & Mattson, M. P. Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function. Proc. Natl Acad. Sci. USA 95, 3227–3232 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Buxbaum, J. D. et al. Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nature Med. 4, 1177–1181 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Leissring, M. A. et al. Calsenilin reverses presenilin-mediated enhancement of calcium signaling. Proc. Natl Acad. Sci. USA 97, 8590–8593 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Putney, J. W. Jr, Broad, L. M., Braun, F. J., Lievremont, J. P. & Bird, G. S. Mechanisms of capacitative calcium entry. J. Cell Sci. 114, 2223–2229 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Van Leuven, F., Dewachter, I., Herms, J. & Godaux, E. APP and PS1 overexpressing and deficient mice: is calcium homeostasis the crux in Alzheimer's disease? Proc. Int. Conf. Alzheimers Dis. Relat. Disord. 8, 911 (2002).

    Google Scholar 

  91. Van Gassen, G., Annaert, W. & Van Broeckhoven, C. Binding partners of Alzheimer's disease proteins: are they physiologically relevant? Neurobiol. Dis. 7, 135–151 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Stabler, S. M., Ostrowski, L. L., Janicki, S. M. & Monteiro, M. J. A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein. J. Cell Biol. 145, 1277–1292 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shinozaki, K. et al. The presenilin 2 loop domain interacts with the μ-calpain C-terminal region. Int. J. Mol. Med. 1, 797–799 (1998).

    CAS  PubMed  Google Scholar 

  94. Pack-Chung, E. et al. Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. J. Biol. Chem. 275, 14440–14445 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Leissring, M. A., Parker, I. & LaFerla, F. M. Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals. J. Biol. Chem. 274, 32535–32538 (1999).Reference 95 shows that clinical mutations in PS2 can also destabilize calcium homeostasis.

    Article  CAS  PubMed  Google Scholar 

  96. Passer, B. et al. Generation of an apoptotic intracellular peptide by γ-secretase cleavage of Alzheimer's amyloid-β protein precursor. J. Alzheimers Dis. 2, 289–301 (2000).Reference 96 was the first study to identify the AICD.

    Article  CAS  PubMed  Google Scholar 

  97. Yu, C. et al. Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment γ. Evidence for distinct mechanisms involved in γ-secretase processing of the APP and Notch1 transmembrane domains. J. Biol. Chem. 276, 43756–43760 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Moehlmann, T. et al. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production. Proc. Natl Acad. Sci. USA 99, 8025–8030 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Weidemann, A. et al. A novel ɛ-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41, 2825–2835 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Gu, Y. et al. Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch. J. Biol. Chem. 276, 35235–35238 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Edbauer, D., Willem, M., Lammich, S., Steiner, H. & Haass, C. Insulin-degrading enzyme rapidly removes the β-amyloid precursor protein intracellular domain (AICD). J. Biol. Chem. 277, 13389–13393 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Kimberly, W. T., Zheng, J. B., Guenette, S. Y. & Selkoe, D. J. The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J. Biol. Chem. 276, 40288–40292 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Fiore, F. et al. The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein. J. Biol. Chem. 270, 30853–30856 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Minopoli, G. et al. The β-amyloid precursor protein functions as a cytosolic anchoring site that prevents Fe65 nuclear translocation. J. Biol. Chem. 276, 6545–6550 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Chow, N., Korenberg, J. R., Chen, X. N. & Neve, R. L. APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein. J. Biol. Chem. 271, 11339–11346 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Borg, J. P., Ooi, J., Levy, E. & Margolis, B. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol. Cell. Biol. 16, 6229–6241 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tanahashi, H. & Tabira, T. X11L2, a new member of the X11 protein family, interacts with Alzheimer's β-amyloid precursor protein. Biochem. Biophys. Res. Commun. 255, 663–667 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Homayouni, R., Rice, D. S., Sheldon, M. & Curran, T. Disabled-1 binds to the cytoplasmic domain of amyloid precursor-like protein 1. J. Neurosci. 19, 7507–7515 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tomita, S. et al. Interaction of a neuron-specific protein containing PDZ domains with Alzheimer's amyloid precursor protein. J. Biol. Chem. 274, 2243–2254 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Matsuda, S. et al. c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK. J. Neurosci. 21, 6597–6607 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tarr, P. E., Roncarati, R., Pelicci, G., Pelicci, P. G. & D'Adamio, L. Tyrosine phosphorylation of the β-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. J. Biol. Chem. 277, 16798–16804 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Russo, C. et al. Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. J. Biol. Chem. 277, 35282–35288 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Gao, Y. & Pimplikar, S. W. The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl Acad. Sci. USA 98, 14979–14984 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zheng, P., Eastman, J., Vande Pol, S. & Pimplikar, S. W. PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein. Proc. Natl Acad. Sci. USA 95, 14745–14750 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Scheinfeld, M. H., Ghersi, E., Laky, K., Fowlkes, B. J. & D'Adamio, L. Processing of β-amyloid precursor like protein-1 and -2 by γ-secretase regulates transcription. J. Biol. Chem. 12 September 2002 (doi:10.1074/jbc.M208110200). | PubMed |

  116. Roncarati, R. et al. The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling. Proc. Natl Acad. Sci. USA 99, 7102–7107 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kinoshita, A., Whelan, C. M., Berezovska, O. & Hyman, B. T. The γ secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells. J. Biol. Chem. 277, 28530–28536 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Veinbergs, I., Mallory, M., Sagara, Y. & Masliah, E. Vitamin E supplementation prevents spatial learning deficits and dendritic alterations in aged apolipoprotein E-deficient mice. Eur. J. Neurosci. 12, 4541–4546 (2000).

    CAS  PubMed  Google Scholar 

  119. Ohm, T. G. et al. Apolipoprotein E and βA4-amyloid: signals and effects. Biochem. Soc. Symp. 67, 121–129 (2001).

    Article  CAS  Google Scholar 

  120. Lalowski, M. et al. The 'nonamyloidogenic' p3 fragment (amyloid β17–42) is a major constituent of Down's syndrome cerebellar preamyloid. J. Biol. Chem. 271, 33623–33631 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Tekirian, T. L. et al. N-terminal heterogeneity of parenchymal and cerebrovascular Aβ deposits. J. Neuropathol. Exp. Neurol. 57, 76–94 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Vassar, R. et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Yang, J. et al. Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels. Proc. Natl Acad. Sci. USA 99, 7711–7716 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).

    Article  CAS  Google Scholar 

  125. Parker, I., Choi, J. & Yao, Y. Elementary events of InsP3-induced Ca2+ liberation in Xenopus oocytes: hot spots, puffs and blips. Cell Calcium 20, 105–121 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Yao, Y., Choi, J. & Parker, I. Quantal puffs of intracellular Ca2+ evoked by inositol trisphosphate in Xenopus oocytes. J. Physiol. (Lond.) 482, 533–553 (1995).

    Article  CAS  Google Scholar 

  127. Sun, X. P., Callamaras, N., Marchant, J. S. & Parker, I. A continuum of InsP3-mediated elementary Ca2+ signalling events in Xenopus oocytes. J. Physiol. (Lond.) 509, 67–80 (1998).

    Article  CAS  Google Scholar 

  128. Leissring, M. A., LaFerla, F. M., Callamaras, N. & Parker, I. Subcellular mechanisms of presenilin-mediated enhancement of calcium signaling. Neurobiol. Dis. 8, 469–478 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Guo, Q. et al. Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. Neuroreport 8, 379–383 (1996).

    Article  CAS  PubMed  Google Scholar 

  130. Begley, J. G., Duan, W., Chan, S., Duff, K. & Mattson, M. P. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J. Neurochem. 72, 1030–1039 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Guo, Q. et al. Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid β-peptide toxicity: central roles of superoxide production and caspase activation. J. Neurochem. 72, 1019–1029 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Gibson, G. E., Zhang, H., Toral-Barza, L., Szolosi, S. & Tofel-Grehl, B. Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease. Biochim. Biophys. Acta 1316, 71–77 (1996).

    Article  PubMed  Google Scholar 

  133. Gibson, G. E., Nielsen, P., Sherman, K. A. & Blass, J. P. Diminished mitogen-induced calcium uptake by lymphocytes from Alzheimer patients. Biol. Psychiatry 22, 1079–1086 (1987).

    Article  CAS  PubMed  Google Scholar 

  134. Hirashima, N. et al. Calcium responses in human fibroblasts: a diagnostic molecular profile for Alzheimer's disease. Neurobiol. Aging 17, 549–555 (1996).

    Article  CAS  PubMed  Google Scholar 

  135. Peterson, C., Ratan, R. R., Shelanski, M. L. & Goldman, J. E. Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors. Proc. Natl Acad. Sci. USA 83, 7999–8001 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Peterson, C., Gibson, G. E. & Blass, J. P. Altered calcium uptake in cultured skin fibroblasts from patients with Alzheimer's disease. N. Engl. J. Med. 312, 1063–1065 (1985).

    Article  CAS  PubMed  Google Scholar 

  137. Peterson, C. & Goldman, J. E. Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proc. Natl Acad. Sci. USA 83, 2758–2762 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Peterson, C., Ratan, R. R., Shelanski, M. L. & Goldman, J. E. Altered response of fibroblasts from aged and Alzheimer donors to drugs that elevate cytosolic free calcium. Neurobiol. Aging 9, 261–266 (1988).

    Article  CAS  PubMed  Google Scholar 

  139. Peterson, C., Ratan, R., Shelanski, M. & Goldman, J. Changes in calcium homeostasis during aging and Alzheimer's disease. Ann. NY Acad. Sci. 568, 262–270 (1989).

    Article  CAS  PubMed  Google Scholar 

  140. Tatebayashi, Y. et al. Cell-cycle-dependent abnormal calcium response in fibroblasts from patients with familial Alzheimer's disease. Dementia 6, 9–16 (1995).

    CAS  PubMed  Google Scholar 

  141. Guo, Q. et al. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17, 4212–4222 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Keller, J. N., Guo, Q., Holtsberg, F. W., Bruce-Keller, A. J. & Mattson, M. P. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J. Neurosci. 18, 4439–4450 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Furukawa, K., Guo, Q., Schellenberg, G. D. & Mattson, M. P. Presenilin-1 mutation alters NGF-induced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells. J. Neurosci. Res. 52, 618–624 (1998).

    Article  CAS  PubMed  Google Scholar 

  144. Popescu, B. O. et al. Caspase cleavage of exon 9 deleted presenilin-1 is an early event in apoptosis induced by calcium ionophore A 23187 in SH-SY5Y neuroblastoma cells. J. Neurosci. Res. 66, 122–134 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Schneider, I. et al. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J. Biol. Chem. 276, 11539–11544 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank M. Leissring and Y. Akbari for their contributions to the original work cited in this manuscript, and F. Van Leuven for discussing unpublished work. I also thank K. Stauderman, C. Glabe, K. Street, G. Stutzmann, J. Shepherd and B. Tseng for critically reading the manuscript, and I. Parker for providing figure 1. Work in my laboratory is supported by grants from the US Public Health Service, the American Health Assistance Foundation and the American Federation of Aging Research.

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Authors and Affiliations

  1. Department of Neurobiology and Behavior, Laboratory of Molecular Neuropathogenesis, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, 92697, California, USA

    Frank M. LaFerla

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DATABASES

LocusLink

APLP1

APLP2

APOE

APP

BACE

BP1

calbindin-D

calmyrin

μ-calpain

calsenilin

disabled 1

E-cadherin

ErbB4

Fe65

InsP3R

insulin-degrading enzyme

JNK-interacting protein

kinesin 1

nicastrin

Notch

Numb

Numb-like

PAT1

PS1

PS2

RyRs

ShcA

ShcC

sorcin

TAU

Tip60

X11

OMIM

Alzheimer's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

Alzheimer disease

amyloidosis

Glossary

IDIOPATHIC

Arising spontaneously or from an unknown cause.

POLYMORPHIC

Occurring in multiple forms. For example, the APOE gene exists as three variants: APOE2, APOE3 and APOE4.

OX-2 ANTIGEN DOMAIN

An antigen domain that is recognized by antibodies to lymphocytes. A member of the immunoglobulin superfamily of cellular adhesion molecules, OX-2 has a major role in the activation of lymphocytes and macrophages.

KUNITZ PROTEASE-INHIBITOR DOMAIN

A functional domain that is common to a large family of proteins — including APP, aprotinin and noggin — that inhibits serine proteases such as trypsin.

HOLOPROTEIN

The full-length, native polypeptide before proteolytic cleavage events that might occur during maturation.

G PROTEIN

A heterotrimeric GTP-binding and -hydrolysing protein that interacts with cell-surface receptors, often stimulating or inhibiting the activity of a downstream enzyme. G proteins consist of three subunits: the α-subunit, which contains the guanine-nucleotide-binding site; and the β- and γ-subunits, which function as a βγ heterodimer.

ATOMIC FORCE MICROSCOPY

A form of microscopy in which a probe is mechanically tracked over a surface of interest in a series of x–y scans. The force found at each coordinate is measured with piezoelectric sensors, providing information about the chemical nature of a surface.

CAPACITATIVE CALCIUM ENTRY

Calcium influx that occurs in response to the depletion of intracellular calcium stores. Calcium enters the cell through specialized store-operated channels in the plasma membrane, allowing depleted calcium stores in the endoplasmic reticulum to be replenished.

IONOPHORE

A substance (natural or synthetic, cyclic or linear) that can bind metal ions in solution and transport them across lipid barriers in natural or artificial membranes.

SERCA PUMP

The sarco-/endoplasmic reticulum calcium ATPase — a pump in the membrane of the endoplasmic reticulum that replenishes calcium stores.

POLYTOPIC

Existing in more than one geographical region.

TYPE 1 TRANSMEMBRANE PROTEIN

An integral membrane polypeptide that extends across the lipid bilayer once, as a single α-helix.

AFTERHYPERPOLARIZATION

The hyperpolarization that ensues after strong depolarization of the membrane.

DOMINANT NEGATIVE

Describes a defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

ADAPTOR PROTEIN

A protein that augments cellular responses by recruiting other proteins to a complex. Adaptor proteins usually contain several protein–protein-interaction domains.

MINIGENE

A sequence that contains all of the elements — such as the alternative exons and the surrounding introns — that are necessary to show the same splicing pattern as the endogenous gene.

PLEIOTROPIC

Able to produce two or more unrelated effects.

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LaFerla, F. Calcium dyshomeostasis and intracellular signalling in alzheimer's disease. Nat Rev Neurosci 3, 862–872 (2002). https://doi.org/10.1038/nrn960

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