Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

Craig Hughes; Minee L. Choi; Jee Hyun Yi; Seung Chan Kim; Anna Drews; Peter St George-Hyslop; Clare Bryant; Sonia Gandhi; Kwangwook Cho; David Klenerman

doi:10.1038/s42003-020-0792-9

Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

Craig Hughes, Minee L. Choi, Jee Hyun Yi, Seung Chan Kim, Anna Drews, Peter St George-Hyslop, Clare Bryant, Sonia Gandhi, Kwangwook Cho, David Klenerman^*

^*Corresponding author for this work

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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.

Original language	English
Article number	79 (2020)
Number of pages	7
Journal	Communications Biology
Volume	3
DOIs	https://doi.org/10.1038/s42003-020-0792-9
Publication status	Published - 18 Feb 2020

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title = "Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death",

abstract = "The molecular events causing memory loss and neuronal cell death in Alzheimer{\textquoteright}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.",

author = "Craig Hughes and Choi, {Minee L.} and Yi, {Jee Hyun} and Kim, {Seung Chan} and Anna Drews and George-Hyslop, {Peter St} and Clare Bryant and Sonia Gandhi and Kwangwook Cho and David Klenerman",

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T1 - Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

AU - Hughes, Craig

AU - Choi, Minee L.

AU - Yi, Jee Hyun

AU - Kim, Seung Chan

AU - Drews, Anna

AU - George-Hyslop, Peter St

AU - Bryant, Clare

AU - Gandhi, Sonia

AU - Cho, Kwangwook

AU - Klenerman, David

PY - 2020/2/18

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N2 - 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.

AB - 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.

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JO - Communications Biology

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Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

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