Whether accumulation of Aβ peptide, hyperphosphorylation of tau, or cell death is generated first in Alzheimer disease, and whether any of these are related, is still a matter of debate. Transgenic mice demonstrating an increased burden of Aβ deposits do not always exhibit hyperphosphorylated tau, and mice overexpressing mutant tau do not exhibit Aβ aggregates. Nevertheless, numerous studies have provided convincing evidence that Aβ and tau are causally related. Indeed, injection of Aβ(1-42) fibrils into P301L tau transgenic mice [1] or rabbit brains [2] accelerates the formation of phosphorylated tau, and transgenic mice overexpressing both mutant amyloid precursor protein and mutant tau exhibit marked neurofibrillary degeneration [3]. Such results are in accordance with in vitro results showing that synthetic Aβ, when added to cultured neurons, leads to increased tau phosphorylation [4-6]. Collectively, these latter results suggest that Aβ accumulation precedes and triggers phosphorylated tau deposition. In accordance are data from the LaFerla group, demonstrating that Aβ...  Read more

Whether accumulation of Aβ peptide, hyperphosphorylation of tau, or cell death is generated first in Alzheimer disease, and whether any of these are related, is still a matter of debate. Transgenic mice demonstrating an increased burden of Aβ deposits do not always exhibit hyperphosphorylated tau, and mice overexpressing mutant tau do not exhibit Aβ aggregates. Nevertheless, numerous studies have provided convincing evidence that Aβ and tau are causally related. Indeed, injection of Aβ(1-42) fibrils into P301L tau transgenic mice [1] or rabbit brains [2] accelerates the formation of phosphorylated tau, and transgenic mice overexpressing both mutant amyloid precursor protein and mutant tau exhibit marked neurofibrillary degeneration [3]. Such results are in accordance with in vitro results showing that synthetic Aβ, when added to cultured neurons, leads to increased tau phosphorylation [4-6]. Collectively, these latter results suggest that Aβ accumulation precedes and triggers phosphorylated tau deposition. In accordance are data from the LaFerla group, demonstrating that Aβ accumulation precedes tangle deposition in a triple transgenic model of AD [7,8].

Additional studies further demonstrate the solid functional link between Aβ and phosphorylated tau. Aβ-induced caspase activation triggers cleavage of tau and generates enhanced polymerized products [9]. Liu and colleagues have also shown that blocking tau expression and phosphorylation with an antisense oligonucleotide completely inhibits Aβ toxicity in differentiated neurons from rat cultures [10]. On the other hand, Rapoport and colleagues have shown that cultured hippocampal neurons expressing either mouse or human tau proteins degenerate in the presence of Aβ fibrils, while tau-depleted neurons show no signs of degeneration [11]. These latter results provide strong evidence that tau expression is required for Aβ-induced neurotoxicity in primary cultures of neurons.

Taken together, although all the above data indicate that Aβ and tau are related and that Aβ accumulation is an upstream event to tau hyperphosphorylation, the mechanistic links underlying Aβ-induced tau phosphorylation are still to be determined.

Now, in this noteworthy article, Michelle King, George Bloom, and colleagues show strong and convincing data that in cells transfected with tau, as well as in primary rat cortical neurons, prefibrillar, but not fibrillar, Aβ42 causes tau to dissociate from microtubules, which then completely and rapidly disassembled. In these experiments, tau appears to make microtubules acutely sensitive to prefibrillar Aβ42. Interestingly, Aβ-induced microtubule disassembly did not correlate with increased tau phosphorylation. These results by King and Bloom may reinforce the hypothesis that Aβ aggregates and phosphorylated tau deposits are less neurotoxic, if not neuroprotective, than prefibrillar Aβ and tau. Confirmation of microtubule disassembly in transgenic mice at a stage before plaque formation takes place will add important insights into intracellular mechanisms that lead to neuronal impairment in Alzheimer disease.

References:
[1] Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001 Aug 24;293(5534):1491-5. Abstract

[2] Ghribi O, Herman MM, Savory J. Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003 Mar 15;71(6):853-62. Abstract

[3] Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. Abstract

[4] Takashima A, Noguchi K, Sato K, Hoshino T, Imahori K. Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7789-93. Abstract

[5] Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, Ishiguro K, Yamaguchi H. Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res. 1998 Aug;31(4):317-23. Abstract

[6] Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J. Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration. FEBS Lett. 1999 Jun 25;453(3):260-4. Abstract

[7] Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging. 2003 Dec;24(8):1063-70. Abstract

[8] Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. Abstract

[9] Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7. Epub 2003 Jul 29. Abstract

[10] Liu T, Perry G, Chan HW, Verdile G, Martins RN, Smith MA, Atwood CS. Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression. J Neurochem. 2004 Feb;88(3):554-63. Abstract

[11] Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6364-9. Epub 2002 Apr 16. Abstract

View all comments by Othman Ghribi

King and colleagues expanded on a previous report by Rapport and colleagues that showed that tau is essential for β amyloid-induced neurotoxicity. In this report, King et al. show that a prefibrillar form of Aβ induced tau-dependent microtubule disassembly. When Aβ neurotoxicity was first reported by Bruce Yankner, researchers in the field discussed whether Aβ could be neurotoxic, because the presence of soluble Aβ showed no neurotoxicity. When it was shown that aged and Congo red-positive fibrillar Aβ showed neurotoxicity, this dispute was settled. Recently, oligomeric Aβ is believed to be a toxic form of Aβ. However, King and colleagues now claim that freshly solubilized Aβ42 and Aβ40 induce the same effect as tau-dependent microtubule disassembly without affecting tau phosphorylation. Although they confirmed that Aβ42 formed an A11 immunoreactive Aβ oligomer, they say that Aβ42 mostly exists as monomers. We still do not know which form of Aβ affects microtubule stability.

Their report raises questions about the role of Aβ in AD development. Aβ forms various aggregate...  Read more

King and colleagues expanded on a previous report by Rapport and colleagues that showed that tau is essential for β amyloid-induced neurotoxicity. In this report, King et al. show that a prefibrillar form of Aβ induced tau-dependent microtubule disassembly. When Aβ neurotoxicity was first reported by Bruce Yankner, researchers in the field discussed whether Aβ could be neurotoxic, because the presence of soluble Aβ showed no neurotoxicity. When it was shown that aged and Congo red-positive fibrillar Aβ showed neurotoxicity, this dispute was settled. Recently, oligomeric Aβ is believed to be a toxic form of Aβ. However, King and colleagues now claim that freshly solubilized Aβ42 and Aβ40 induce the same effect as tau-dependent microtubule disassembly without affecting tau phosphorylation. Although they confirmed that Aβ42 formed an A11 immunoreactive Aβ oligomer, they say that Aβ42 mostly exists as monomers. We still do not know which form of Aβ affects microtubule stability.

Their report raises questions about the role of Aβ in AD development. Aβ forms various aggregate structures. Do these different aggregates activate different mechanisms that lead to neurotoxicity? For example, could some aggregates directly induce apoptosis, while other aggregates affect microtubule stability? If diffusible Aβ aggregates induce tau-dependent microtubule disassembly that leads to neuronal dysfunction, why would symptoms of AD start with impairment of entorhinal/hippocampal function where there is no Aβ deposition? Based on the β amyloid hypothesis, Aβ directly affects neurons and induces neuronal dysfunction with NFT formation and neuronal loss. Tau-dependent microtubule disassembly may contribute to neuronal dysfunction before neuronal death and the formation of NFTs through synapse loss as Paul Coleman mentioned. However, Aβ deposition does not start in the entorhinal/hippocampal region in the AD brain (although APP Tg mice start from the hippocampal region and memory impairment). Even if it is not fibrillar Aβ but diffusible Aβ aggregates that lead to neuronal dysfunction, it is difficult to explain the emergence of AD symptoms by pointing to a specific neuronal dysfunction. We may need a more practical explanation for the development of AD.

View all comments by Akihiko Takashima