Amyloid oligomer interactions and polymorphisms: disease-relevant distinct assembly of α-synuclein and tau

Neurodegenerative diseases are complex diseases characterized by set of disease-specific clinical symptoms with one or more characteristic protein aggregates. However, there has been considerable overlap between multiple diseases, both in terms of clinical manifestations and protein accumulation [1]. The co-occurrence of α-synuclein and tau protein pathologies in several brain diseases implies a toxic relationship and has become an active area of research. Two of the major challenges faced in the neurodegeneration field are the formation and biological relevance of amyloid polymorphisms (strains) and the toxic interactions between amyloidogenic proteins [2]. Previously, we demonstrated that, in addition to the meta-stable oligomeric α-synuclein, tau oligomers are also present in Parkinson’s disease and Dementia with Lewy bodies [3].

In our recent study, we presented novel evidence supporting the role of α-synuclein potentiating the harmful effects of tau [4]. We demonstrated that tau aggregates induced by pre-formed α-synuclein oligomers evade larger aggregate or fibril formation, thus, prolonging their oligomeric state compared to the self-aggregated tau. We evaluated the seeding propensity of tau oligomers prepared with or without pre-formed α-synuclein oligomers by exogenously adding them in three different cell models: YFP-tau expressing CV-1 cells, differentiated human neuroblastoma cell line SH-SY5Y and primary cortical neurons from embryos of Htau mouse, a transgenic tauopathy mouse model. Pre-formed α-synuclein oligomers induced tau aggregates were more potent in altering cell morphology and increasing cell death in CV-1 and SH-SY5Y cells. Moreover, these aggregates caused significant dendritic spine retraction in primary neurons when compared to the self-aggregated tau, indicating the differences in their seeding properties and toxic effects. Therefore, to gain more insight into the toxic interaction between α-synuclein and tau, we isolated complexes of oligomeric α-synuclein and tau from post-mortem Parkinson’s disease (PD) brain tissues, and tau oligomers from brain tissues of progressive supranuclear palsy (PSP), a pure tauopathy without any documented α-synuclein pathology. Upon administration of these brain-derived aggregates into Htau mice, α-synuclein-tau complexes accelerated endogenous tau aggregation, caused memory deficits and spread disease pathologies as compared to pure tau oligomers.

Our study demonstrates the combined deleterious effects of α-synuclein and tau, suggesting a toxic mechanism of interaction. The ability of oligomeric α-synuclein to induce tau aggregation also points to the mechanism of cross-seeding, which has been observed among several amyloidogenic proteins, including Aβ in multiple neurodegenerative diseases [5]. This is in accordance with our previous observation, where oligomeric aggregates of Aβ, PrP, α-synuclein and TDP-43 proteins are shown to co-localize in AD pathology [6]. In conclusion, our study represents the first step to elucidate the toxic interplay between α-synuclein and tau altering the aggregation profiles and nature of amyloid deposits, possibly, resulting in the formation of unique aggregates that can cause specific loss of functions of important proteins and impairment of cellular machineries. Insights into the pathogenic interaction between α-synuclein and tau will lead to further investigation of their upstream or downstream interacting proteins that may also have potential roles in disease pathologies. This will lay the groundwork for more successful therapeutic interventions by targeting multiple candidate molecules, such as α-synuclein and tau in diseases.

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Acknowledgements

We thank all the members of Kayed laboratory for their helpful insights, suggestions and support. This work was supported by the Michael J. Fox foundation, the Gillson Longenbaugh Foundation, the Mitchell Center for Neurodegenerative Diseases, the Sealy Center for Vaccine Development and the NIH grants AG054025 (R.K.), NS094557 (R.K.) and AG055771 (R.K.).

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Correspondence to Rakez Kayed.

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Sengupta, U., Kayed, R. Amyloid oligomer interactions and polymorphisms: disease-relevant distinct assembly of α-synuclein and tau. Neuropsychopharmacol 44, 222–223 (2019). https://doi.org/10.1038/s41386-018-0204-8

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