Pickett EK, Herrmann AG, McQueen J, Abt K, Dando O, Tulloch J, Jain P, Dunnett S, Sohrabi S, Fjeldstad MP, Calkin W, Murison L, Jackson RJ, Tzioras M, Stevenson A, d'Orange M, Hooley M, Davies C, Colom-Cadena M, Anton-Fernandez A, King D, Oren I, Rose J, McKenzie CA, Allison E, Smith C, Hardt O, Henstridge CM, Hardingham GE, Spires-Jones TL. Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease. Cell Rep. 2019 Dec 10;29(11):3592-3604.e5. PubMed.
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University College London
Recent work has begun to challenge the long-held view that Aβ and tau sequentially contribute to Alzheimer’s disease (AD), and has provided evidence that both protein types may significantly interact with each other during the disease. This new study by Pickett et al. reinforces the emerging idea that there is synergy between Aβ and tau and that this interaction accelerates disease progression. The work further corroborates recent evidence that soluble tau species rather than neurofibrillary tangles are critical for the synergistic effects (Busche, 2019).
Pickett et al. compared the behavioral and gene expression effects of (wild-type) tau and Aβ present in the brains of APP/PS1-rTg21221-crossed mice with the effects in the original parental lines, rTg21221 and APP/PS1, which exhibit the same expression levels and spatial distribution patterns in the brain. Intriguingly, the APP/PS1-tau crosses showed a marked behavioral hyperactivity phenotype, along with a strong reduction in neuronal and synaptic gene expression. (Individually, the APP/PS1 transgene appears to upregulate neuroinflammatory genes, whereas the tau transgene alone did not have a strong impact on gene expression). Of note, the cellular prion protein was upregulated in the APP/PS1-tau crosses, consistent with a recent study that identified the cellular prion protein as a potential intermediate/contributor to Aβ/tau synergy (Gomes et al., 2019).
Another interesting observation is that the APP/PS1-tau crosses had a lower plaque burden compared with APP/PS1 siblings, suggesting that the presence of tau may in some manner modulate local Aβ plaque characteristics. Indeed, several other studies support an effect of tau (or a tau-related event) on plaque formation, possibly via microglial activation (Bennett et al., 2017; Chen et al., 2016).
Finally, the authors reported that tau transgene suppression reduced the behavioral hyperactivity and prevented the further downregulation of gene expression in the APP/PS1-rTg21221. However, it is important to note that the tau suppression did not restore normal gene expression in the mice, and also did not reduce the observed gliosis, suggesting that tau suppression might be less effective in the presence of Aβ. This finding is in line with our previous work in a similar APP/PS1-tau model, which was characterized by neuronal hypoactivity, showing that in the presence of Aβ, tau suppression was less effective in restoring normal neuronal activities (Busche et al., 2019). We think these experimental findings have relevance for clinical trial design, and in particular the prospects of anti-Aβ or anti-tau monotherapies.
Several questions remain. For example, additional work is necessary to better understand the cellular and circuit basis of the hyperactivity phenotype in the APP/PS1-rTg21221 mice and, crucially, how it translates to human disease. Furthermore, the mechanisms underlying the Aβ/tau synergy remain unknown, although the current study suggests that the synergy may not be due to a physical interaction between At and tau, since the two proteins do not appear to co-localize in cellular processes and synapses. We believe that elucidating this important issue is urgently needed to accelerate the development of effective treatments for AD.
References:
Bennett RE, DeVos SL, Dujardin S, Corjuc B, Gor R, Gonzalez J, Roe AD, Frosch MP, Pitstick R, Carlson GA, Hyman BT. Enhanced Tau Aggregation in the Presence of Amyloid β. Am J Pathol. 2017 Jul;187(7):1601-1612. Epub 2017 May 10 PubMed.
Busche MA. Tau suppresses neuronal activity in vivo, even before tangles form. Brain. 2019 Apr 1;142(4):843-846. PubMed.
Busche MA, Wegmann S, Dujardin S, Commins C, Schiantarelli J, Klickstein N, Kamath TV, Carlson GA, Nelken I, Hyman BT. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci. 2019 Jan;22(1):57-64. Epub 2018 Dec 17 PubMed.
Chen W, Abud EA, Yeung ST, Lakatos A, Nassi T, Wang J, Blum D, Buée L, Poon WW, Blurton-Jones M. Increased tauopathy drives microglia-mediated clearance of beta-amyloid. Acta Neuropathol Commun. 2016 Jun 23;4(1):63. PubMed.
Gomes LA, Hipp SA, Rijal Upadhaya A, Balakrishnan K, Ospitalieri S, Koper MJ, Largo-Barrientos P, Uytterhoeven V, Reichwald J, Rabe S, Vandenberghe R, von Arnim CA, Tousseyn T, Feederle R, Giudici C, Willem M, Staufenbiel M, Thal DR. Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Acta Neuropathol. 2019 Dec;138(6):913-941. Epub 2019 Aug 14 PubMed.
Katholieke Universiteit Leuven, Department of Imaging and Pathology, Laboratory of Neuropathology
KU Leuven
During the last years, we have seen growing evidence that cooperation between pathological proteins may be a key element in the pathogenesis of a variety of neurodegenerative diseases, with the most recent example being a study showing accelerated spreading of α-syn in the presence of Aβ plaques in APP transgenic mice (Bassil et al., 2019).
Here, Pickett et al. studied the pathological cooperation between Aβ and tau in a mouse model expressing an APP/PS1 transgene on a tau knockout background with a doxycycline-related reversible expression of wild-type human tau (APP/PS1+Tau). The authors found behavioral and transcriptional deficits in APP/PS1+Tau mice that were restored by lowering tau levels. Interestingly, they found synergy between Aβ and tau to downregulate expression of genes involved in synapse function, whereas upregulation was mostly occurring independently. The fact that many upregulated inflammatory markers expressed by glial cells were reduced with tau partial suppression suggests that tau might also be involved in the increased inflammatory response that has been attributed to Aβ.
Together, these results support the hypothesis that the interplay between Aβ and tau is necessary for the development of the full-blown picture of AD. Independently, these proteins might be already responsible for certain toxic effects, but only when they co-occur does disease progression significantly accelerate and lead to the appearance of cognitive symptoms of AD. Therefore, studies like this one, exploring the mechanisms of Aβ and tau cooperation, are essential for the progress of the field and our understanding of AD as a multifactorial complex disorder.
The authors’ observation that PrPC is upregulated in APP/PS1+Tau mice in a tau-dependent manner is very interesting. Very recent reports by Corbett et al. (2019) and us (Gomes et al., 2019) provided further evidence for a role of PrPC in AD. We were able to show that both Aβ and p-tau interact with PrPC, which was associated with an Aβ-accelerated spreading of tau in APP-transgenic mice (Gomes et al., 2019). Corbett et al. extended this knowledge by showing binding of soluble Aβ, α-syn and tau to PrPC in vitro and in vivo (Corbett et al., 2019).
Taken together, there is more and more evidence that the interplay of Aβ and tau in the pathogenesis of AD is a major critical event, with probably PrPC as a central player. Since α-syn also interacts with PrPC (Corbett et al., 2019), and its spreading is accelerated by Aβ (Bassil et al., 2019), a similar PrPC-linked mechanism of protein collaboration can be speculated.
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