Abstract
Alzheimer’s disease (AD) is neuropathologically marked by the presence of senile plaques composed of β-amyloid peptide and by neurofibrillary tangles formed by abnormally phosphorylated tau protein. Many authors have also reported a neuronal loss in affected regions of the brain in AD patients. This neuronal degeneration could be linked to the triggering of intracellular pathways leading to apoptosis. Previous works were focused on the links between neuronal apoptosis and tau and amyloid precursor protein (APP) metabolisms. We have analyzed tau gene expression in primary neuronal cultures submitted to an apoptotic stress produced by excitotoxicity or serum deprivation. Glutamate induces an enhancement of tau gene expression in resistant neurons whereas a reduced expression is noted in apoptotic cells. This decrease is similar to what is observed after trophic support withdrawal in neuronal cultures. Neurons expressing phosphorylated tau are more resistant to experimental apoptosis than neurons positively labeled for de- phosphorylated tau protein (AT8/Tau 1 epitope). In vitro apoptotic neurons are able to produce membrane blebbings (strongly immunopositive for APP and amyloidogenic fragments) that are secondary released in the extracellular space. Finally neurons overexpressing human mutated presenilin 1 (M146 L) are more prone to degenerate than neurons overexpressing human wild-type presenilin 1 after apoptosis induction. Alzheimer’s disease (AD) is neuropathologically marked by the presence of senile plaques containing an accumulation of the β-amyloid peptide, by neurofibrillary tangles made of intraneuronal hyperphosphorylated tau protein and also by neuronal loss observed by a majority of authors. The cause of neuronal death in AD is unknown although a growing body of evidence suggests that the accumulation of extracellular (and/or intracellular) (3- amyloid peptide could trigger a toxic neuronal degeneration. Trying to find out the origin of neuronal loss in AD is a crucial point since this could lead to the introduction of neuroprotective strategies in future treatments of this disease. Of course this prospective could also be applied to all neurodegenerative diseases. Recent findings suggest that apoptosis could play a role in cell loss detected in AD although this issue is still debated among physicians and medical scientists. This short review will focus on apoptosis and cellular and transgenic model of AD.
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References
Canu N, Dus L, Barbato C, Ciotti MT, Brancolini C, Rinaldi AM, Novak M, Cattaneo A, Bradbury A, Calissano P (1998) Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. J Neurosci 18: 7061 – 7074
Chiu DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T (1999) Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med 5: 560 – 564
Czech C, Lesort M, Tremp G, Terro F, Blanchard V, Schombert B, Carpentier N, Dreisler S, Bonici B, Takashima A, Moussaoui S, Hugon J, Pradier L (1998) Characterization of human presenilin 1 transgenic rats: increased sensitivity to apoptosis in primary neuronal cultures. Neurosci 87: 325 – 336
Delacourte A, Buee L (1997) Normal and pathological Tau proteins as factors for microtubule assembly. Int Rev Cytol 171: 167 – 224
Esclaire F, Terro F, Yardin C, Hugon J (1998) Neuronal apoptosis is associated with a decrease in tau mRNA expression. NeuroReport 9: 1173 – 1177
Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, Leblanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid- beta precursor protein and amyloidogenic a beta peptide formation. Cell 97: 395 – 406
Guo Q, Sopher BL, Furukawa K, Pham DG, Robinson N, Martin GM, Mattson MP (1997) Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid (3-peptide: involvement of calcium and oxyradicals. J Neurosci 17: 4212 – 4222
Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP (1998) Par 4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer’s disease. Nat Med 4: 957 – 962
Hugon J, Esclaire F, Lesort M (1999) Toxic neuronal apoptosis and modifications of tau and APP gene and protein expressions. Drug Met Rev 31: 635 – 647
Laferla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G (1995) The Alzheimer’s amyloid β-peptide induces neurodegeneration and apoptosis cell death in transgenic mice. Nat Genet 9: 21 – 30
Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, Wisniewski HM (1995) Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ. Acta Neuropathol 89: 35 – 41
Leblanc A (1995) Increased production of 4kDa amyloid β-peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis. J Neurosci 15: 7837 – 7846
Leblanc A, Liu H, Goodyer C, Bergeron C, Hammond J (1999) Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer’s disease. J Biol Chem 274: 23426 – 23436
Lesort M, Blanchard C, Yardin C, Esclaire F, Hugon J (1997a) Cultured neurons expressing phosphorylated tau are more resistant to apoptosis induced by NMD A or serum deprivation. Mol Brain Res 45: 127–132 Lesort M, Terro F, Esclaire F, Hugon J (1997b) Neuronal APP accumulates in toxic membrane blebbings. J Neural Transm 104: 497 – 513
Marcus DL, Strafaci JA, Miller DC, Masia S, Thomas CG, Rosman J, Hussain S, Freed- man ML (1998) Quantitative neuronal c-fos and c-jun expression in Alzheimer’s disease. Neurobiol Aging 19: 393 – 400
Mattson MP (1994) Calcium and neuronal injury in Alzheimer’s disease. Contributions of β-amyloid precursor protein mismetabolism, free radicals, and metabolic compromise. Ann NY Acad Sci 15: 50 – 76
Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, Younkin S, Duff K, Hardy J, Hutton M (1998) Increased amyloid β-42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol 43: 256 – 258
Migheli A, Cavalla P, Marino S, Schiffer D (1994) A study of apoptosis in normal and pathologic nervous tissue after in situ end — labeling of DNA strand breaks. J Neuropathol Exp Neurol 53: 606 – 616
Passer BJ, Pellegrini L, Vito P, Ganjei JK, D’Adamio L (1999) Interaction of Alzheimer’s presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death. J Biol Chem 274: 24007 – 24013
Pellegrini L, Passer BJ, Tabaton M, Ganjei JK, D’Adamio L (1999) Alternative, non- secretase processing of Alzheimer’s beta-amyloid precursor protein during apoptosis by caspase-6 and 8. J Biol Chem 274: 21011 – 21016
Roperch JP, Alvaro V, Prieur S, Tuynder M, Nemani M, Lethrosne F, Piouffre L, Gendron MC, Israeli D, Dausset J, Oren M, Amson R, Telerman A (1998) Inhibition of presenilin 1 expression is promoted by p53 and p21 WAF1 and results in apoptosis and tumor suppression. Nat Med 4: 835 – 838
Stadelmann C, Bruck W, Bancher C, Jellinger K, Lassmann H (1998) Alzheimer’s disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 57: 456 – 464
Su JH, Anderson AJ, Cummings BJ, Cotman CW (1994) Immunohistochemical evidence for apoptosis in Alzheimer’s disease. NeuroReport 5: 2529 – 2533
Uetsuki T, Takemoto K, Nishimura I, Okamoto M, Niinobe M, Momoi T, Miura M, Yoshikawa K (1999) Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein. J Neurosci 19: 6955 – 6964
Van de Craen M, De Jonghe C, Van Den Brande I, Declercq W, Van Gassen G, Van Criekinge W, Vanderhoeven I, Fiers W, Van Broeckhoven C, Hendriks L, Vandenabeele P (1999) Identification of caspases that cleave presenilin-1 and presenilin-2, five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases. FEBS Lett 445: 149 – 154
Vito P, Wolozin B, Ganjei JK, Iwasaki K, Lacana E, D’Adamio L (1996) Requirement of the familial Alzheimer’s disease gene PS2 for apoptosis. Opposing effect of ALG-3. J Biol Chem 271: 31025 – 31028
Weidemann A, Paliga K, Drrwang U, Reinhard FB, Schuckert O, Evin G, Masters CL (1999) Proteolytic processing of the Alzheimer’s disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases. J Biol Chem 274: 5823 – 5829
Weihl CC, Ghadge GD, Kennedy SG, Hay N, Miller RJ, Roos RP (1999) Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB. J Neurosci 19: 5360 – 5369
Wolozin B, Iwasaki K, Vito P, Ganjei JK, Lacana E, Sunderland T, Zhao B, Kusiak JW, Wasco W, D’Adamio L (1996) Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274: 1710 – 1713
Zubenko GS, Stiffler JS, Hughes HB, Martinez AJ (1999) Reduction in brain phos- phatidylinositol kinase activities in Alzheimer’s disease. Biol Psychiatry 45: 731 – 736
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Hugon, J., Terro, F., Esclaire, F., Yardin, C. (2000). Markers of apoptosis and models of programmed cell death in Alzheimer’s disease. In: Jellinger, K., Schmidt, R., Windisch, M. (eds) Advances in Dementia Research. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6781-6_15
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DOI: https://doi.org/10.1007/978-3-7091-6781-6_15
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