In Lewy body (LB) diseases, including Parkinson’s disease (PD), without and with dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) patients with LB co-pathology1, α-synuclein (α-Syn) aggregates in neurons as LBs and Lewy neurites (LNs)2, while in multiple system atrophy (MSA), α-Syn mainly accumulates in oligodendrocytes as glial cytoplasmic inclusions (GCIs)3. Here, we report that pathological α-Syn in GCIs and LBs (GCI-α-Syn and LB-α-Syn) are conformationally and biologically distinct. GCI-α-Syn forms more compact structures and is ~1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of MSA. Surprisingly, GCI-α-Syn and LB-α-Syn show no cell type preference in seeding α-Syn pathology, raising the question of why they demonstrate different cell type distributions in LB disease versus MSA. Strikingly, we found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.
Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque-associated tau pathogenesis.
Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies. Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease. This heterogeneity could be due to tau aggregates forming distinct structural conformations, or strains. We now report the development of a sporadic tauopathy model to study human tau strains by intracerebrally injecting nontransgenic mice with pathological tau enriched from human tauopathy brains. We show human tau strains seed different types and cellular distributions of tau neuropathology in our model that recapitulate the heterogeneity seen in these human diseases.
Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically-connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, factors regulating spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here, we use quantitative pathology mapping in the mouse brain combined with network modeling to understand the spatiotemporal pattern of spread. α-Synuclein pathology patterns are well-described by a network model based on two factors—anatomical connectivity and endogenous α-Synuclein expression. The map and model allow assessment of selective vulnerability to α-Synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor impacts the spread and toxicity of α-Synuclein pathology.
The deposition of misfolded β-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of conformationally diverse strains as a common property for multiple amyloidogenic proteins including α-Synuclein (α-Syn). α-Syn is misfolded and aggregated in a group of neurodegenerative diseases collectively known as α-Synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy body, multiple system atrophy and also a subset of Alzheimer's disease patients with concomitant PD-like Lewy bodies and neurites. While sharing the same pathological protein, different α-Synucleinopathies demonstrate distinct clinical and pathological phenotypes, which could result from the existence of diverse pathological α-Syn strains in patients. In this review, we summarized the characteristics of different α-Synucleinopathies and α-Syn strains generated with recombinant α-Syn monomers. We also make predictions of α-Syn strains that could potentially exist in patients based on the knowledge from other amyloid proteins and the clinical and pathological features of different α-Synucleinopathies.
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