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Resting microglia react to Aβ42 fibrils but do not detect oligomers or oligomer-induced neuronal damage.

Abstract：

:In Alzheimer's disease (AD), amyloid-β (Aβ) deposits accumulate in the brain parenchyma and contain fibrils of aggregated heterogeneous Aβ peptides. In addition to fibrils, Aβ aggregates into stable soluble species (termed Aβ oligomers), which are increasingly viewed as the key drivers of early neurodegenerative events in AD. Aβ aggregates stimulate microglia recruitment and activation. In the AD brain, microglia surround Aβ deposits, activate, and abnormally produce inflammatory mediators, contributing to AD pathogenesis. However, it remains unclear to which of the conformationally diverse Aβ species microglia specifically react. Here, we explore the "sensor" capability of murine microglia. We examine whether they can detect and discriminate the toxic Aβ oligomers, Aβ fibrils, and Aβ-induced neuronal damage and investigate whether they are activated by diverse human Aβ species cell autonomously or through neuron-derived factors. We find that, on aggregation in vitro, Aβ42 peptides form stable oligomers and fibrils, which are neurotoxic and trigger dendritic spine loss in mature primary mouse hippocampal neurons. Further, in resting primary murine microglia, Aβ42 fibrils induce a pattern of expression of inflammatory genes typical of the classical inflammatory response induced by infectious agents (e.g., the bacterial toxin lipopolysaccharide). Conversely, Aβ42 oligomers never elicit a microglia inflammatory response, whether applied alone, in combination with neuron-derived secreted factors, or in contact with neurons. Thus, microglia strongly react to Aβ42 fibrils, but do not sense Aβ oligomers or oligomer-induced neuronal damage. This suggests that early neurotoxic species can escape detection by microglia, leading to the chronic unfolding of amyloid pathology in AD.

journal_name

Neurobiol Aging

journal_title

Neurobiology of aging

authors

Ferrera D,Mazzaro N,Canale C,Gasparini L

doi

10.1016/j.neurobiolaging.2014.05.023

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

2444-2457

issue

eissn

0197-4580

issn

1558-1497

pii

S0197-4580(14)00386-8

journal_volume

pub_type

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Resting microglia react to Aβ42 fibrils but do not detect oligomers or oligomer-induced neuronal damage.