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.
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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.
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Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation.
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