Activated microglia mediate synapse loss and short-term memory deficits in a mouse model of transthyretin-related oculoleptomeningeal amyloidosis

Abstract

Oculoleptomeningeal amyloidosis (OA) is a fatal and untreatable hereditary disease characterized by the accumulation of transthyretin (TTR) amyloid within the central nervous system. The mechanisms underlying the pathogenesis of OA, and in particular how amyloid triggers neuronal damage, are still unknown. Here, we show that amyloid fibrils formed by a mutant form of TTR, A25T, activate microglia, leading to the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nitric oxide. Further, we found that A25T amyloid fibrils induce the activation of Akt, culminating in the translocation of NFκB to the nucleus of microglia. While A25T fibrils were not directly toxic to neurons, the exposure of neuronal cultures to media conditioned by fibril-activated microglia caused synapse loss that culminated in extensive neuronal death via apoptosis. Finally, intracerebroventricular (i.c.v.) injection of A25T fibrils caused microgliosis, increased brain TNF-α and IL-6 levels and cognitive deficits in mice, which could be prevented by minocycline treatment. These results indicate that A25T fibrils act as pro-inflammatory agents in OA, activating microglia and causing neuronal damage.

Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain

“…Regardless of the mechanism(s) of action, our current findings are in contrast to the microglial inhibition and neuroprotection reported in many previous rodent studies using similar doses of minocycline (30–90 mg/kg; studies referenced above as well as more recent findings by Ma et al, ; Reinebrant et al, ; Azevedo et al, ; Kobayashi et al, ; Yin et al, ; Peng et al, ). The present observations are in accord, however, with those of two recent studies reporting increased cell death specifically in layer V of the mouse sensorimotor or somatosensory cortex following neonatal minocycline treatment (Ueno et al, ; Arnoux et al, ).…”

Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma–induced retinal pathology

“…Two inflammatory cytokines (IL-1β and IL-6) implicated in neuronal apoptosis (Azevedo et al, 2013; Guadagno et al, 2015) are known to be regulated by ERβ engagement in brain microglia (Saijo et al, 2011). For this reason, we examined IL-1β (Fig.…”

Plasma and cerebrospinal fluid amyloid-β levels in late-life depression: A systematic review and meta-analysis

“…A recent animal study showed that the injection of amyloid-β oligomers leads to depressive-like phenomena in mice (Ledo et al , 2013). Also, the deposition of Aβ in the brain leads to microglial activation, increased pro-inflammatory markers, and reduced neurotrophic support (Azevedo et al , 2013). These changes are observed in both AD and LLD subjects (Thorsell et al , 2010; Naismith et al , 2012).…”