Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015 Nov;18(11):1584-93. Epub 2015 Oct 5 PubMed.
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Mayo Clinic Florida
Thank you for the encouraging comments and critiques on our article. Regarding the species of tau transmitting in this study, the propagated tau was immunoreactive to oligomer-specific antibody (T22), and we saw more AT8+ tau at a later stage, which is commonly seen in the brain of advanced AD stage, although these were thioflavin-S negative. We agree that further studies are necessary.
One interesting topic raised by these comments is whether neurofibrillary tangle formation is necessary for neurodegeneration. There is a clear disconnect between neuronal cell loss and neurofibrillary tangle formation as reported in the rTg4510 mouse model (Santacruz et al., 2005; Spires et al., 2006). This demonstrates that neuronal cell loss precedes NFT formation, thus NFT is not necessarily toxic to neurons.
Indeed, others reported that NFT-bearing neurons maintain excitability as determined by whole-cell path clamp recording of cortical neurons of rTg4510 mice (Crimins et al., 2011). On the other hand, tau oligomer is neurotoxic and can propagate in wild-type mouse brain (Lasagna-Reeves et al., 2010; Lasagna-Reeves et al., 2012). Thus, non-fibril tau can propagate and is toxic to neurons, demonstrating the biological importance of non-fibril tau in pathobiology of AD.
References:
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15;309(5733):476-81. PubMed.
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.
Crimins JL, Rocher AB, Peters A, Shultz P, Lewis J, Luebke JI. Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy. Acta Neuropathol. 2011 Nov;122(5):551-64. PubMed.
Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R. Preparation and characterization of neurotoxic tau oligomers. Biochemistry. 2010 Nov 30;49(47):10039-41. Epub 2010 Nov 8 PubMed.
Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Kiritoshi T, Neugebauer V, Jackson GR, Kayed R. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep. 2012;2:700. PubMed.
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