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Microglia contribute to the propagation of Abeta pathology into healthy brain tissue

ABSTRACT: The extracellular accumulation of amyloid-beta (A) peptides is a major hallmark of Alzheimer’s disease (AD). It is widely accepted that microglia associate with A plaques and appear morphologically activated especially in their immediate vicinity. Whether microglia play a role in A plaque formation and contribute to the propagation of A pathology remains however unknown. We therefore investigated the characteristics of microglia during neural transplantation experiments where wild-type neurons are grafted into the cortex of AD mouse models. Here, we demonstrate that A from the transgenic host tissue is able to enter and deposit within wild-type (WT) grafts, a process that is accompanied by massive microglia infiltration. Notably, manipulation of microglia function or microglia elimination significantly reduced A deposition within the grafts. Similarly, time-lapse in vivo two-photon imaging revealed that microglia transport A to the site of injury thereby identifying microglia as cellular carrier of A that propagate A pathology in previously unaffected CNS tissue. Our data thus argue for a hitherto unexplored mechanism of A propagation.

ORGANISM(S): Mus musculus

PROVIDER: GSE162920 | GEO | 2022/01/27

REPOSITORIES: GEO

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Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.

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Microglia contribute to the propagation of Abeta pathology into healthy brain tissue

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