Amyloid beta-induced signalling in leptomeningeal cells and its impact on astrocyte response

Abstract

The pathological signature of Alzheimer's disease (AD) includes the accumulation of toxic protein aggregates, mainly consisting of amyloid beta (Aβ). Recent strides in fundamental research underscore the pivotal role of waste clearance mechanisms in the brain suggesting it may be an early indication of early onset AD. This study delves into the involvement of leptomeningeal cells (LMCs), crucial components forming integral barriers within the clearance system, in the context of AD. We examined the inflammatory cytokine responses of LMCs in the presence of Aβ, alongside assessments of LMC growth response, viability, oxidative stress, and changes in vimentin expression. The LMCs showed no changes in growth, viability, oxidative stress, or vimentin expression in the presence of Aβ, indicating that LMCs are less susceptible to Aβ damage compared to other CNS cells. However, LMCs exhibited a unique pro-inflammatory response to Aβ when compared to an LPS inflammatory control, showing an mRNA expression of pro-inflammatory cytokines such IL-6, IL-10 and IL-33 but no changes in IL-1α and IL-1β. Furthermore, LMCs influenced the astrocyte response to Aβ, as conditioned media from Aβ-treated LMCs was observed to downregulate somatic S100β in astrocytes. We also investigated whether the JAK/STAT3 pathway was involved in the Aβ response of the LMCs, as this pathway has been shown to be activated in astrocytes and neurons in the presence of Aβ. JAK/STAT3 activation was assessed through phosphorylated STAT3, revealing that JAK/STAT3 was not active in the cells when in the presence of Aβ. However, when JAK1 and JAK2 were inhibited, cytokine protein levels of IL7, IL10, IL15 and IL33 levels, which had shown alteration when LMCs were treated with Aβ, returned to base levels. This indicates that although JAK1/STAT3 and JAK2/STAT3 are not the direct pathway for Aβ response in LMCs, JAK1 and JAK2 may still play a role in regulating cytokine levels, potentially through indirect means or crosstalk. Overall, our findings reveal that LMCs are resilient to Aβ toxicity and suggest that JAK1/STAT3 and JAK2/STAT3 does not play a central role in the inflammatory response, providing new insights into the cellular mechanisms underlying AD.

Keywords: Alzheimer’s disease; Astrocytes; JAK/STAT pathway; Leptomeningeal cells; Meninges.