Clustering of Tau fibrils impairs the synaptic composition of α3‐Na ⁺ /K ⁺ ‐ ATP ase and AMPA receptors

Abstract

Tau assemblies have prion‐like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion‐like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+‐ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3‐NKA and an increase in the amount of GluA2‐AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and α‐synuclein aggregates often co‐exist in patients’ brains. We now show evidences for cross‐talk between these pathogenic aggregates with α‐synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar α‐synuclein and Tau cross‐talk at the plasma membrane imbalance neuronal homeostasis.

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

“…In vitro, even if a few studies showed that extracellular tau may bind to neuronal receptors (muscarinic [83], Na + / K + ATPase (NKA) [161]…) and have toxic effects, most have shown that incubated aggregates/seeds are internalized by endocytosis and promote aggregation of overexpressed tau in cell lines [66,75,86,93,94,134,135,148,156,[170][171][172]. Nevertheless, most seeding assays use transfection reagents and thus bypass receptor-mediated endocytosis, which may be a critical step in prion-like propagation.…”

Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders

“…Impaired NMDAR-dependent hippocampal LTP or enhanced LTD are observed in various transgenic AD animal models (Mango et al, 2019 ). Tau protein appears to be involved in synaptic removal of AMPARs, as clustering of tau fibrils reduced synaptic abundance of AMPARs (Shrivastava et al, 2019 ). Moreover, Tau protein phosphorylation was involved in a ketamine-induced reduction in surface expression of AMPARs in hippocampal neurons (Li et al, 2019 ).…”

“…Mitochondria, as energy centers and calcium buffer organelles, may play an important role in the regulation of synaptic plasticity (Todorova and Blokland, 2017 ). Moreover, PD dementia is considered a convergence of α-synuclein, tau, and Aβ pathologies (Irwin et al, 2013 ; Shrivastava et al, 2019 ). As discussed in the AD section, both tau and Aβ appear to be involved in the removal of synaptic AMPARs (Jurado, 2018 ; Li et al, 2019 ; Shrivastava et al, 2019 ).…”

“…Moreover, PD dementia is considered a convergence of α-synuclein, tau, and Aβ pathologies (Irwin et al, 2013 ; Shrivastava et al, 2019 ). As discussed in the AD section, both tau and Aβ appear to be involved in the removal of synaptic AMPARs (Jurado, 2018 ; Li et al, 2019 ; Shrivastava et al, 2019 ). Thus, PD-related dementia might involve dysregulation of AMPAR trafficking induced by Aβ and tau.…”

Polypeptides derived from α-Synuclein binding partners to prevent α-Synuclein fibrils interaction with and take-up by cells

“…The fibrils bind laterally to the plasma membrane [13]. The binding is mediated by interaction with the plasma membrane lipids [22], with different proteins partners [23][24][25][26] and with the extra cellular matrix components [27,28]. The efficiency of the binding depends both on the aggregates characteristics, such as their primary sequence [29,30], their net charge [22], their size [13] or their conformation [17], and on the properties of the membrane, with an emphasis on the role of the membrane curvature [31] and a specific lipid [32] and protein [24,25] composition.…”