Differential cross-seeding properties of tau and α-synuclein in mouse models of tauopathy and synucleinopathy

Abstract

<jats:title>Abstract</jats:title> <jats:p>Co-occurrence of tau and α-synuclein pathologies in a subset of Alzheimer’s disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer’s disease neurodegenerative cascade. To understand the etiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant α-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of tau fibrils or α-synuclein fibrils, and to a lesser extent tau+α-synuclein copolymer fibrils prepared from co-incubating individual recombinant monomers, induced robust phosphorylated tau pathology in PS19 mice relative to control mice. Though the tau+α-synuclein copolymer fibrils did not modulate induction of pathologies at the site of injection, examination of the whole brain showed that these copolymers exacerbated neuroanatomic transmission of seeded tau pathology compared to tau fibril injected mice. Only α-synuclein fibrils, but not tau alone or tau+α-synuclein copolymers, triggered modest levels of endogenous phosphorylated α-synuclein pathology. Overall, data from the PS19 mice suggests that human α-synuclein fibrils can efficiently cross-seed human tau and has a modest priming effect on mouse α-synuclein, and the presence of tau fibrils does not exacerbate the priming process. In M20 mice, unilateral hippocampal injection of α-synuclein fibrils or tau fibrils induced robust bilateral phosphorylated α-synuclein pathology, while tau+α-synuclein copolymer injection resulted in restricted phosphorylated α-synuclein pathology predominantly in the ipsilateral cortex. This suggests that human tau fibrils can also induce human α-synuclein pathogenesis, and the presence of combinatorial seeds is not synergistic. None of these aggregates induced phosphorylated tau pathology in M20 mice, showing that mouse tau cannot be primed efficiently by human tau fibrils or human α-synuclein fibrils. Neuropathological analysis of the whole brain of M20 mice showed that tau+α-synuclein copolymer injected mice had lower abundance of bilaterally transmitted α-synuclein pathologies relative to α-synuclein fibril injected mice. Thus, the tau+α-synuclein copolymer fibrils show robust transmission properties preferentially in rodent model of tauopathies but not in synucleinopathy, probably signifying an enhanced cooperative relationship between tau and α-synuclein in the tau seeding process. Together, our data highlights the unique cross-seeding properties of tau and αSyn in neurodegenerative proteinopathies.</jats:p>

The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

“…It is likely that Alzheimer co-pathology contributes towards the development of dementia in Lewy-body positive cases, since two concomitant neurodegenerative diseases are most likely worse than one. Moreover, in vitro and in vivo studies have shown that amyloid-␤ and tau fibrils can induce ␣-synuclein monomers to aggregate [112,113]. Approximately 10% of cognitively normal people at 50 years are amyloid-␤ positive, rising to 33% at 80 years [114].…”

Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential

“…Treatment of oligodendrocytes and its precursors with exogenous α-Syn aggregates increases the low level of endogenous α-Syn by templating the formation of stable α-Syn aggregates [44,44,65], and this has been hypothesised to represent a neuron-oligodendroglial pathway of importance for MSA [43]. MSA brain extracts and in particular the detergent-insoluble fraction containing the α-Syn filaments are more potent seeds of α-Syn aggregation in cellular and in vivo models [79,89,108,114,115]. This potency can be propagated in laboratory animals and is one reason why MSA has been proposed to represent a distinct prion-like disease [79,108,114,115].…”

“…MSA brain extracts and in particular the detergent-insoluble fraction containing the α-Syn filaments are more potent seeds of α-Syn aggregation in cellular and in vivo models [79,89,108,114,115]. This potency can be propagated in laboratory animals and is one reason why MSA has been proposed to represent a distinct prion-like disease [79,108,114,115]. Mounting evidence supports that the α-Syn aggregation in oligodendrocytes represents the key to MSA brain extracts being potent inducers of α-Syn aggregation in disease models [77].…”

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

“…482 Fibrils composed from both Tau and a-synuclein monomers showed differential pathology propagation when injected into the mouse brain, where Tauopathy was induced at higher levels than synucleinopathy. 483 Both Tau and a-synuclein have been implicated in pathology spreading through anatomically connected brain regions in a protein strain-specific manner, resulting in distinct disease phenotypes in humans (reviewed in ref. 484 and 485).…”