He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, Zhang B, Gathagan RJ, Yue C, Dengler C, Stieber A, Nitla M, Coulter DA, Abel T, Brunden KR, Trojanowski JQ, Lee VM. Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018 Jan;24(1):29-38. Epub 2017 Dec 4 PubMed.

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  1. Based on pathological chronology and genetic evidence, I and others have postulated that Aβ is like the Mafia boss and tau is the hitman. The question is, how does Aβ amyloidosis induce tauopathy? In a previous study, a team led by Brad Hyman showed that crossing tau transgenic mice with APP/PS1 transgenics accelerated tau propagation (Pooler et al., 2015), so there is indeed a connection between Aβ amyloidosis and tauopathy. What is new in this latest Nature Medicine paper by Virginia Lee’s group? They indicate that, at early seeding stages, Aβ plaques facilitate tau accumulation in the neuritic plaques rather than neurofibrillary tangle formation. This may lead to a major paradigm shift, because neuritic dystrophies generally have been considered nonspecific accumulations of axonal proteins at pre-synapses. So, the effort to understand the Aβ-tau axis has moved one step further. One remaining question is why it takes Aβ amyloidosis approximately two decades to induce tauopathy in human brain (Bateman et al., 2012). To understand how the initial tau seeds are made may be a key to answer this question.

    References:

    Pooler AM, Polydoro M, Maury EA, Nicholls SB, Reddy SM, Wegmann S, William C, Saqran L, Cagsal-Getkin O, Pitstick R, Beier DR, Carlson GA, Spires-Jones TL, Hyman BT. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease. Acta Neuropathol Commun. 2015 Mar 24;3:14. PubMed.

    Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. PubMed.

    View all comments by Takaomi Saido

  2. This is an exciting paper that nicely explores how Aβ interacts to enhance tau pathology using a model system that overcomes some of the limitations of transgenic mice. In work from our lab, we recently reported that Aβ pathology interacts with tau to form more pathological tau seeds earlier on in the disease course. The findings from He et al. complement this research by demonstrating that Aβ can also spatially alter tau pathology, shifting the balance toward neuritic dystrophy tau or neurofibrillary tangle tau depending on disease stage. I think the spatio-temporal dynamic between these two hallmark pathologies is fascinating and can help explain key observations from neuropathological examination of AD cases showing Aβ in the cortical mantle precedes tau tangle formation.

    I think further studies to address what forms of tau are present and how these may be differentially altered by Aβ will be exciting to look into and the results of these studies would have clear therapeutic implications. It will be interesting to determine if this neuritic-plaque-tau-to-neurofibriallary-tangle pathological progression is typical in AD or if preparing tau extracts from additional cases and brain regions will yield different results. 

    View all comments by Rachel Bennett

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