Parkinson’s Disease (PD) involves not only α-synuclein pathology in dopaminergic neurons but also vascular impairments that remain underexplored due to limitations of traditional in vitro models. Here we present a microengineered 3D neurovascular midbrain model that reconstructs the capillary interface of substantia nigra dopaminergic neurons. In our proof-of-concept demonstration, we successfully recapitulated neuronal pathology in PD, including α-synuclein aggregation, inflammatory responses, and progressive neuronal degeneration, by exposing our model to specially generated PD-associated α-synuclein preformed-fibrils. Importantly, this engineering approach also enables the investigation of progressive vascular abnormalities in PD, such as endothelial dysfunction, barrier disruption, vascular regression, and the resulting impairment of blood flow. Our PD model establishes a tractable platform for investigating the multifaceted nature of the disease and understanding the complex interplay between neurodegeneration and vascular pathology, offering a unique tool for developing innovative therapeutic strategies that address both the neuronal and vascular components of PD pathology.

A variety of strain sensors have been developed to measure internal deformations of elastomeric structures. Strain sensors measuring extremely small mechanical strain, however, have not yet been reported due mainly to the inherently intrusive integration of the sensor with the test structure. In this work, we report the development of a minimally intrusive, highly sensitive mechanical strain transducer realized by monolithically embedding a Fabry-Pérot (FP) etalon into a poly(dimethylsiloxane) (PDMS) block test structure. Due to the extreme sensitivity of the FP resonance condition to the thickness of the spacer layer between the two reflectors, the limit of detection in the mechanical deformation can be as low as ~110 nm with a 632.8 nm laser used as the probing light. The compatibility of PDMS with additive fabrication turned out to be the most crucial enabling factor in the realization of the FP etalon-based strain transducer.

Parkinson’s Disease (PD) is primarily characterized by α-synuclein pathology, which manifests as intraneuronal inclusions, neuroinflammation, and neurodegeneration. However, emerging evidence also points to significant vascular impairments as a critical aspect of PD pathology, which remains largely underexplored due to the inability of traditional in vitro models to recapitulate such vascular changes. To address this unmet need, here we combine the human organ-on-a-chip technology with the principle of vasculogenic self-assembly to engineer the capillary interface of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. In our proof-of-concept demonstration, we successfully recreated critical neuronal pathology in PD, including α-synuclein aggregation, inflammatory responses, and progressive neuronal degeneration, by exposing our model to specially generated PD-associated α-synuclein preformed fibrils. Importantly, this engineering approach also enables the investigation of progressive vascular changes characteristic of PD, such as endothelial dysfunction, barrier disruption, and vascular regression. Our sophisticated PD model establishes a novel platform for exploring the multifaceted nature of the disease and understanding the complex interplay between neurodegeneration and vascular pathology, offering a unique tool for developing innovative therapeutic strategies that address both the neuronal and vascular components of PD pathology.

Neurodegenerative diseases are increasingly associated with vascular dysfunction beyond progressive neuronal degeneration, yet how vascular pathology contributes to disease progression remains poorly understood, largely due to the lack of a neurodegenerative disease model capable of capturing neuronal pathology alongside associated vascular dysfunction. Here, we developed a microengineered 3D vascularized brain tissue model that integrates neurospheroids with a self-assembled, perfusable vascular network to recapitulate key features of the neurovascular interface. Using this model, we investigated the vascular contribution to Parkinson’s disease pathology by introducing α-synuclein preformed fibrils into the engineered vasculature. Intravascular α-syn fibril exposure induced endothelial barrier disruption, vascular leakage, inflammation, and vascular regression. Notably, this vascular insult was accompanied by intraneuronal α-synuclein aggregation within neurospheroids, suggesting that vascular dysfunction may facilitate the exposure of neural tissue to pathogenic α-synuclein. Our neurodegenerative disease modeling approach establishes a versatile and tractable platform for investigating vascular contributions to neurodegenerative disease progression.

The frequent coexistence of α-synuclein (α-syn) and amyloid-β (Aβ) aggregates in neurodegenerative diseases suggests that heterotypic interactions between these amyloidogenic proteins may influence disease progression, yet their molecular consequences remain poorly understood. Here, we investigated how distinct aggregation states of Aβ42, monomers and preformed fibrils (PFFs), modulate α-syn fibril formation, structure, and downstream neuronal pathology. Thioflavin T kinetics showed that Aβ42 monomers delayed α-syn fibril formation, whereas Aβ42 PFFs exhibited a trend toward accelerated aggregation, indicating aggregation state-dependent effects on α-syn aggregation. Negative-stain TEM, proteinase K digestion, and solid-state NMR spectroscopy further demonstrated that both Aβ42 monomers and PFFs altered α-syn fibril structure, generating distinct fibril conformations depending on the Aβ42 concentration and aggregation state. To determine whether these conformational differences influence pathological activity, α-syn PFF variants generated in the presence of different concentrations of Aβ42 monomers or PFFs were applied to dopaminergic neuronal cells. α-Syn fibrils formed in the presence of Aβ42 PFFs showed greater capacity to induce intraneuronal α-syn aggregation than α-syn PFFs, whereas fibrils formed in the presence of Aβ42 monomers exhibited similar or reduced intraneuronal aggregation-inducing capacity relative to α-syn PFFs. Together, our findings demonstrate that heterotypic interactions with Aβ42 reshape α-syn aggregation pathways and fibril conformations, generating structurally distinct α-syn fibril populations that vary in their ability to trigger intraneuronal aggregation. These results provide a molecular framework for understanding how cross-talk between amyloidogenic proteins may contribute to structural and pathological heterogeneity in mixed neurodegenerative diseases.