Abstract
The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD.
Highlights
The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown
There is no significant cell death for total monomer concentrations below 40 nM (Supplementary Fig. 2). We found that both BV2 microglial cell line and astrocytes showed a sensitized response with time and this was significant at oligomer concentrations down to 10 pM (Fig. 2), but there was no measurable response in Toll-like receptor 4 (TLR4) and Myd[88] knockout cell lines (Supplementary Fig. 3)
Here we have shown using rat neuron and glial cells that Aβ aggregates cause long term potentiation (LTP) deficit and neuronal cell death predominantly by an autocrine/paracrine mechanism due to the production of pro-inflammatory cytokines, predominantly by TLR4 signalling by glial cells we cannot rule out some contribution from neurons in the LTP deficit experiment
Summary
The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown. We explored if this aggregateinduced inflammatory response could lead to LTP deficit and neuronal cell death, cellular correlates of the symptoms associated with the development of AD, by performing experiments in the presence and absence of TLR4 antagonists.
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