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Schaler AW, Runyan AM, Clelland CL, Sydney EJ, Fowler SL, Figueroa HY, Shioda S, Santa-Maria I, Duff KE, Myeku N. PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain. Sci Transl Med. 2021 May 26;13(595) PubMed.
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The University of Minnesota
Under physiological conditions, the microtubule-associated protein tau is enriched in axons but mostly devoid in postsynaptic structures such as the soma and dendrites, leading to a polarized cellular distribution of tau.
One common mechanism underlying multiple neurodegenerative diseases, including Alzheimer’s and frontotemporal dementia, involves the redistribution of tau from the axon into the somatodendritic compartments of neurons, leading to loss of tau polarity. The loss of polarity is followed by mislocalization of tau into dendritic spines, the postsynaptic structures found in most excitatory glutamatergic synapses, and by subsequent postsynaptic deficits. Although intensively studied, the cellular mechanisms by which pathogenic triggers, such as Aβ or disease-linked tau mutations, cause the postsynaptic accumulation of tau remain unknown.
In this elegant manuscript, Schaler et al. reported a novel PAC1 receptor-mediated signaling cascade that leads to the loss and/or reversal of tau polarity in animal models of frontotemporal dementia. They also reported that toxic postsynaptic tau species mediate the propagation to tau pathologies across cells. The study is of high translational significance because changes in tau polarity are one of the most commonly reported features in tauopathies, and the unraveled signaling cascade might be exploited to treat AD and other neurodegenerative diseases.
Mechanistically, it will be exciting to determine which step PAC1 receptors are involved in: tau redistribution to the somatodendritic domain, or subsequent tau mislocalization to dendritic spines.
View all comments by Dezhi LiaoUniversity Clinic Cologne
This paper by Schaler et al. provides valuable insight into the contribution of postsynaptic pathological tau to disease progression in the rTg4510 mouse model. The authors, led by Natura Myeku, convincingly show that postsynaptic mutant tau is the main driver in synaptic and behavioral dysfunction, and that postsynaptic tau may be more pathological than presynaptic tau, which they demonstrate in a careful way in different assays. Notably, increased clearance of pathological tau, induced by PACAP-mediated increase in proteasomal degradation, markedly reduced disease severity.
This paper emphasizes that dendritic and postsynaptic tau may be the main driver of neuronal dysfunction in most tauopathies, and that increasing (postsynaptic) clearance may be beneficial in many disease paradigms.
This goes in line with our past findings clearly showing that tau mislocalization into the dendrites and dendritic spines (tau mis-sorting) is causative for neuronal dysfunction, and that sorting mechanisms usually targeting tau to the axons fail in disease paradigms of Alzheimer disease and related tauopathies (see e.g., Zempel et al., 2013; Zempel et al., 2017; Zempel and Mandelkow, 2014; Zempel and Mandelkow, 2019).
Schaler et al. provide an important proof of concept, yet the important limitation of this study is the huge overexpression of mutant tau in the rTg4510 mouse (more than 10x), and that only one isoform of tau is expressed. We recently confirmed that different isoforms of tau show a significantly different axodendritic distribution, and that their functional effect (in our case on cellular microtubules) may be different (Bachmann et al., 2021). In line with the data presented here, we also hypothesize that dendritic and postsynaptic tau drives the disease, but for tau to reach the dendrites, the sorting mechanism must fail early in disease.
Using iPSC- and SH-SY5Y cell-derived human neurons, we recently showed that successful targeting of tau to the axon may depend less than previously thought on the Axon Initial Segment (AIS), the neuronal polarity orchestrator in neurons (Bell et al., 2021). In combination with the data presented here by Schaler et al., it is fairly clear that apart from tau aggregates and modifications, aberrant tau localization should be considered a disease driver in future studies and therapeutic approaches.
References:
Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H, Mandelkow E, Mandelkow EM. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013 Nov 13;32(22):2920-37. PubMed.
Zempel H, Dennissen FJ, Kumar Y, Luedtke J, Biernat J, Mandelkow EM, Mandelkow E. Axodendritic sorting and pathological missorting of Tau are isoform-specific and determined by axon initial segment architecture. J Biol Chem. 2017 Jul 21;292(29):12192-12207. Epub 2017 May 23 PubMed.
Zempel H, Mandelkow E. Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci. 2014 Dec;37(12):721-32. Epub 2014 Sep 12 PubMed.
Zempel H, Mandelkow E. Mechanisms of Axonal Sorting of Tau and Influence of the Axon Initial Segment on Tau Cell Polarity. Adv Exp Med Biol. 2019;1184:69-77. PubMed.
Bachmann S, Bell M, Klimek J, Zempel H. Differential Effects of the Six Human TAU Isoforms: Somatic Retention of 2N-TAU and Increased Microtubule Number Induced by 4R-TAU. Front Neurosci. 2021;15:643115. Epub 2021 May 25 PubMed.
Bell M, Bachmann S, Klimek J, Langerscheidt F, Zempel H. Axonal TAU Sorting Requires the C-terminus of TAU but is Independent of ANKG and TRIM46 Enrichment at the AIS. Neuroscience. 2021 May 1;461:155-171. Epub 2021 Feb 6 PubMed.
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