Spires TL, Orne JD, Santacruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT.
Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy.
Am J Pathol. 2006 May;168(5):1598-607.
PubMed.
A host of papers now indicates that neurofibrillary tangles (NFTs) are not a major cause of neuron death. These include an earlier paper by Brad Hyman as well as a paper by Renee Morsch, Bill Simon and me that concluded that neurons live for decades after they have formed NFTs. Although NFTs may not be a major cause of neuron death, they certainly contribute to decreased functional capacity of single neurons as well as synaptic deficits.
This is a well-described, interesting study. Together with studies mentioned above by P. Coleman, it is quite likely that neurofibrillary tangles (NFTs) of paired helical filaments (PHFs) themselves do not cause neuronal death in the diseased brain. Instead, formation of highly polymerized NFTs from the unpolymerized, abnormally hyperphosphorylated tau may be a defense mechanism of the affected neurons by which they turn the cytotoxic soluble hyperphosphorylated tau into inert NTFs (Alonso and Iqbal, 2005; Gong et al., 2006).
Several studies have demonstrated that unpolymerized hyperphosphorylated tau is neurotoxic, probably due to its sequestering normal tau and other microtubule-associated proteins and, thus, disrupting microtubules (Alonso et al., 1994; 1996; 1997; 2001; Fath et al., 2002), whereas upon polymerization into PHFs/NFTs, tau loses this toxic activity and becomes biologically and pathologically inert (Alonso et al., 2006). This may also explain why some NFT-containing neurons can survive for many years to decades (Morsch et al., 1999).
We have to distinguish the role between abnormally hyperphosphorylated tau and NFTs in the pathogenesis of tauopathies. This and other studies exclude a major role of NFTs in neuronal loss, but do not exclude such a role of the abnormally hyperphosphorylated tau. Actually, the hyperphosphorylated tau is toxic not only in vitro (Alonso et al., 1994; 1996; 1997; 2001), but also in vivo (Wittmann et al., 2001; Jackson et al., 2002). Hyperphosphorylation of tau at different phosphorylation sites has distinct effects on its loss of normal biological activity, its gain of toxic activity, and promoting tau’s self-assembly into PHFs. For example, phosphorylation sites at the middle part of tau (Ser199/Ser202/Thr205, Thr212, Thr231/Ser235, Ser262/Ser356) are critical to convert normal tau to a toxic molecule, whereas phosphorylation at the C-terminus of tau, including the PHF-1 sites (Ser396/Ser404), mainly promotes tau self-assembly into filaments (Abraha et al., 2000; Ferrari et al., 2003; Alonso et al., 2004; Haase et al., 2004). Because accumulated tau, both in human tauopathies and in all animal models of tauopathy, is always hyperphosphorylated, it is very possible that the neurodegeneration seen in these transgenic mouse brains results from unpolymerized hyperphosphorylated tau, whereas polymerization of this toxic tau into inert PHFs/NFTs is the neurons’ self-defense mechanism for survival.
Therefore, this study does not exclude a role of abnormal hyperphosphorylation of tau in neurodegeneration. Future studies on the correlation between time- and region-specific neurodegeneration and the level of unpolymerized hyperphosphorylation of tau, especially at those sites critical to toxicity, in this or transgenic mice with tauopathies, will no doubt provide new insight into the mechanism of tau-mediated neurodegeneration.
References:
Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, Binder LI.
C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease.
J Cell Sci. 2000 Nov;113 Pt 21:3737-45.
PubMed.
del C Alonso A, Iqbal K.
Tau-induced neurodegeneration: a clue to its mechanism.
J Alzheimers Dis. 2005 Dec;8(3):223-6.
PubMed.
Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K.
Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments.
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8. Epub 2001 May 29
PubMed.
Alonso AC, Grundke-Iqbal I, Iqbal K.
Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules.
Nat Med. 1996 Jul;2(7):783-7.
PubMed.
Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K.
Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease.
Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5562-6.
PubMed.
Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K.
Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau.
Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):298-303.
PubMed.
Alonso Ad, Li B, Grundke-Iqbal I, Iqbal K.
Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity.
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8864-9.
PubMed.
Alonso Ad, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K.
Promotion of hyperphosphorylation by frontotemporal dementia tau mutations.
J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9
PubMed.
Fath T, Eidenmüller J, Brandt R.
Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease.
J Neurosci. 2002 Nov 15;22(22):9733-41.
PubMed.
Ferrari A, Hoerndli F, Baechi T, Nitsch RM, Götz J.
beta-Amyloid induces paired helical filament-like tau filaments in tissue culture.
J Biol Chem. 2003 Oct 10;278(41):40162-8.
PubMed.
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K.
Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation.
J Alzheimers Dis. 2006 Mar;9(1):1-12.
PubMed.
Haase C, Stieler JT, Arendt T, Holzer M.
Pseudophosphorylation of tau protein alters its ability for self-aggregation.
J Neurochem. 2004 Mar;88(6):1509-20.
PubMed.
Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH.
Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila.
Neuron. 2002 May 16;34(4):509-19.
PubMed.
Morsch R, Simon W, Coleman PD.
Neurons may live for decades with neurofibrillary tangles.
J Neuropathol Exp Neurol. 1999 Feb;58(2):188-97.
PubMed.
Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB.
Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles.
Science. 2001 Jul 27;293(5530):711-4. Epub 2001 Jun 14
PubMed.
Comments
Banner Research Institute
A host of papers now indicates that neurofibrillary tangles (NFTs) are not a major cause of neuron death. These include an earlier paper by Brad Hyman as well as a paper by Renee Morsch, Bill Simon and me that concluded that neurons live for decades after they have formed NFTs. Although NFTs may not be a major cause of neuron death, they certainly contribute to decreased functional capacity of single neurons as well as synaptic deficits.
New York State Institute for Basic Research
This is a well-described, interesting study. Together with studies mentioned above by P. Coleman, it is quite likely that neurofibrillary tangles (NFTs) of paired helical filaments (PHFs) themselves do not cause neuronal death in the diseased brain. Instead, formation of highly polymerized NFTs from the unpolymerized, abnormally hyperphosphorylated tau may be a defense mechanism of the affected neurons by which they turn the cytotoxic soluble hyperphosphorylated tau into inert NTFs (Alonso and Iqbal, 2005; Gong et al., 2006).
Several studies have demonstrated that unpolymerized hyperphosphorylated tau is neurotoxic, probably due to its sequestering normal tau and other microtubule-associated proteins and, thus, disrupting microtubules (Alonso et al., 1994; 1996; 1997; 2001; Fath et al., 2002), whereas upon polymerization into PHFs/NFTs, tau loses this toxic activity and becomes biologically and pathologically inert (Alonso et al., 2006). This may also explain why some NFT-containing neurons can survive for many years to decades (Morsch et al., 1999).
We have to distinguish the role between abnormally hyperphosphorylated tau and NFTs in the pathogenesis of tauopathies. This and other studies exclude a major role of NFTs in neuronal loss, but do not exclude such a role of the abnormally hyperphosphorylated tau. Actually, the hyperphosphorylated tau is toxic not only in vitro (Alonso et al., 1994; 1996; 1997; 2001), but also in vivo (Wittmann et al., 2001; Jackson et al., 2002). Hyperphosphorylation of tau at different phosphorylation sites has distinct effects on its loss of normal biological activity, its gain of toxic activity, and promoting tau’s self-assembly into PHFs. For example, phosphorylation sites at the middle part of tau (Ser199/Ser202/Thr205, Thr212, Thr231/Ser235, Ser262/Ser356) are critical to convert normal tau to a toxic molecule, whereas phosphorylation at the C-terminus of tau, including the PHF-1 sites (Ser396/Ser404), mainly promotes tau self-assembly into filaments (Abraha et al., 2000; Ferrari et al., 2003; Alonso et al., 2004; Haase et al., 2004). Because accumulated tau, both in human tauopathies and in all animal models of tauopathy, is always hyperphosphorylated, it is very possible that the neurodegeneration seen in these transgenic mouse brains results from unpolymerized hyperphosphorylated tau, whereas polymerization of this toxic tau into inert PHFs/NFTs is the neurons’ self-defense mechanism for survival.
Therefore, this study does not exclude a role of abnormal hyperphosphorylation of tau in neurodegeneration. Future studies on the correlation between time- and region-specific neurodegeneration and the level of unpolymerized hyperphosphorylation of tau, especially at those sites critical to toxicity, in this or transgenic mice with tauopathies, will no doubt provide new insight into the mechanism of tau-mediated neurodegeneration.
References:
Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, Binder LI. C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J Cell Sci. 2000 Nov;113 Pt 21:3737-45. PubMed.
del C Alonso A, Iqbal K. Tau-induced neurodegeneration: a clue to its mechanism. J Alzheimers Dis. 2005 Dec;8(3):223-6. PubMed.
Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8. Epub 2001 May 29 PubMed.
Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med. 1996 Jul;2(7):783-7. PubMed.
Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5562-6. PubMed.
Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):298-303. PubMed.
Alonso Ad, Li B, Grundke-Iqbal I, Iqbal K. Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8864-9. PubMed.
Alonso Ad, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.
Fath T, Eidenmüller J, Brandt R. Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. J Neurosci. 2002 Nov 15;22(22):9733-41. PubMed.
Ferrari A, Hoerndli F, Baechi T, Nitsch RM, Götz J. beta-Amyloid induces paired helical filament-like tau filaments in tissue culture. J Biol Chem. 2003 Oct 10;278(41):40162-8. PubMed.
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis. 2006 Mar;9(1):1-12. PubMed.
Haase C, Stieler JT, Arendt T, Holzer M. Pseudophosphorylation of tau protein alters its ability for self-aggregation. J Neurochem. 2004 Mar;88(6):1509-20. PubMed.
Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron. 2002 May 16;34(4):509-19. PubMed.
Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol. 1999 Feb;58(2):188-97. PubMed.
Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science. 2001 Jul 27;293(5530):711-4. Epub 2001 Jun 14 PubMed.
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