Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species

Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson’s disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reacti...

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Bibliographic Details
Authors: Sirerol‑Piquer, María Salomé, Pérez Villalba, Ana, Duart-Abadia, Pere, Belenguer, Germán, Gómez-Pinedo, Ulises, Blasco-Chamarro, Laura, Carrillo‑Barberà, Pau, Pérez‑Cañamás, Azucena, Navarro-Garrido, Victoria, Dehay, Benjamin, Vila, Miquel, Vitorica, Javier, Pérez-Sánchez, Francisco, Fariñas, Isabel
Format: article
Publication Date:2025
Country:España
Institution:Universidad Católica de Valencia San Vicente Mártir
Repository:RIUCV. Repositorio de la Universidad Católica de Valencia San Vicente Mártir
Language:English
OAI Identifier:oai:riucv.ucv.es:20.500.12466/5661
Online Access:http://hdl.handle.net/20.500.12466/5661
Access Level:Open access
Keyword:Alpha-synuclein
Microglia
Aging
Parkinson’s disease
Lewy bodies
61 Psicología
32 Ciencias Médicas
Description
Summary:Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson’s disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the recently uncovered microglial molecular diversity. Here, we show that periventricular microglia of the subependymal neurogenic niche monitor the cerebrospinal fluid and can rapidly phagocytize and degrade different aggregated forms of αSyn delivered into the lateral ventricle. However, this clearing ability worsens with age, leading to an increase in microglia with aggregates in aged treated mice, an accumulation also observed in human PD samples. We also show that exposure of aged microglia to aggregated αSyn isolated from human PD samples results in the phosphorylation of the endogenous protein and the generation of αSyn seeds that can transmit the pathology to healthy neurons. Our data indicate that while microglial phagocytosis rapidly clears toxic αSyn, aged microglia can contribute to synucleinopathy spreading.

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