Dataset Information

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

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets