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

Commun Biol. 2020 Feb 18;3(1):79. doi: 10.1038/s42003-020-0792-9.

Authors

Craig Hughes^#¹, Minee L Choi^#^{2

3}, Jee-Hyun Yi^#^{4

5}, Seung-Chan Kim^{4

6}, Anna Drews^{1

7}, Peter St George-Hyslop⁸, Clare Bryant⁹, Sonia Gandhi^{2

3}, Kwangwook Cho^{4

6}, David Klenerman^{10

11}

Affiliations

¹ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
³ The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁴ Centre for Synaptic Plasticity, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol, BS1 3NY, UK.
⁵ Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, 34126, Republic of Korea.
⁶ UK-Dementia Research Institute at King's College London, King's College, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 9NU, UK.
⁷ The German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, Venusberg-Campus, Gebäude 99, 53127, Bonn, Germany.
⁸ Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus The Keith Peters Building Hills Road, Cambridge, CB2 0XY, UK.
⁹ Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK.
¹⁰ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. dk10012@cam.ac.uk.
¹¹ UK Dementia Research Institute, University of Cambridge, Cambridge, CB2 0XY, UK. dk10012@cam.ac.uk.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / pharmacology
Amyloid beta-Peptides / physiology*
Animals
Animals, Newborn
Cell Death / drug effects
Cells, Cultured
Embryo, Mammalian
Long-Term Potentiation / drug effects
Male
Mice
Neurons / drug effects
Neurons / physiology*
Protein Aggregates / physiology*
Protein Aggregation, Pathological / metabolism
Protein Aggregation, Pathological / physiopathology
Protein Aggregation, Pathological / psychology
Rats
Rats, Sprague-Dawley
Rats, Wistar
Signal Transduction / drug effects
Toll-Like Receptor 4 / metabolism

Substances

Amyloid beta-Peptides
Protein Aggregates
Toll-Like Receptor 4

Abstract

Publication types

MeSH terms

Substances

Grants and funding