. Divergent pathways mediate spine alterations and cell death induced by amyloid-beta, wild-type tau, and R406W tau. J Neurosci. 2009 Nov 18;29(46):14439-50. PubMed.

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  1. This result is puzzling. In our hands, crossbreeding of APPTg and R406W tau or wild-type tau Tg did not enhance neurodegeneration (unpublished data).
    FTDP17 mutant tau induces neurodegeneration without showing Abeta deposition. I would caution that the results in this study may not reflect neurodegeneration in vivo, and lack some proper controls.

  2. I believe the anti-TNF Alzheimer's studies authored by Edward Tobinick and mentioned in this story are spurious.

    View all comments by Gerard Roberts
  3. Tackenberg and Brandt showed that Aβ is involved in synapse loss, and that hyperphosphorylated tau is involved in neuronal death, using primary neuronal cultures. However, there are discrepancies from our previous report analyzing wild-type human tau Tg mouse, which indicated that the mouse did not show neurofibrillary tangles (NFTs) and neuronal loss, but that hyperphosphorylated tau is involved in synapse loss, leading to memory impairment due to reducing neural activity in the entorhinal cortex (1).

    We also crossbred human wild-type tau Tg mouse with an APP Tg mouse. However, this double Tg mouse did not show neuronal loss or NFTs, either. One explanation for the discrepancies between our and the authors’ findings is that the effects of Aβ and tau might be different in cultured neurons, and neurons in brain.

    Finally, the authors expressed EGFP-tau in neurons, and counted synaptic density. Tau is microtubule-binding protein but the authors detected EGFP-tau fluorescence in dendritic spines Does this mean that tau localized to the dendritic spines?

    The authors’ hypothesis, that Aβ affects wild-type and mutant (R406W) tau toxicity by different pathways downstream of NMDAR activity, could explain why tau-deficient neurons are resistant to Aβ neurotoxicity (2), but could not explain why tau deficiency improves Aβ-induced memory impairment (3).

    References:

    . Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human tau. EMBO J. 2007 Dec 12;26(24):5143-52. PubMed.

    . Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6364-9. PubMed.

    . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.