Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice

Evelyn Medawar; Tiffanie A Benway; Wenfei Liu; Taylor A Hanan; Peter Haslehurst; Owain T James; Kenrick Yap; Laurenz Muessig; Fabia Moroni; Muzammil A Nahaboo Solim; Gaukhar Baidildinova; Rui Wang; Jill C Richardson; Francesca Cacucci; Dervis A Salih; Damian M Cummings; Frances A Edwards

doi:10.1016/j.ebiom.2018.12.006

Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APP_Swe/PSEN1_M146V transgenic mice

EBioMedicine. 2019 Jan:39:422-435. doi: 10.1016/j.ebiom.2018.12.006. Epub 2018 Dec 13.

Authors

Evelyn Medawar¹, Tiffanie A Benway², Wenfei Liu³, Taylor A Hanan⁴, Peter Haslehurst⁵, Owain T James⁴, Kenrick Yap⁴, Laurenz Muessig⁶, Fabia Moroni⁴, Muzammil A Nahaboo Solim⁷, Gaukhar Baidildinova⁸, Rui Wang⁹, Jill C Richardson¹⁰, Francesca Cacucci¹¹, Dervis A Salih¹², Damian M Cummings¹³, Frances A Edwards¹⁴

Affiliations

¹ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: medawar@cbs.mpg.de.
² Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: tiffanie.benway@smallpharma.co.uk.
³ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: wenfei.liu.10@ucl.ac.uk.
⁴ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
⁵ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: peter.haslehurst@pharm.ox.ac.uk.
⁶ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: l.mussig@ucl.ac.uk.
⁷ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.; Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.. Electronic address: muzammil.solim.09@ucl.ac.uk.
⁸ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.; Department of Science and Innovations, Asfendiyarov Kazakh National Medical University, Zhamakayev Street, Almaty, A26P6B5, Kazakhstan.
⁹ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: r.wang@ucl.ac.uk.
¹⁰ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: jill.richardson1@merck.com.
¹¹ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: f.cacucci@ucl.ac.uk.
¹² Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: dervis.salih@ucl.ac.uk.
¹³ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: d.cummings@ucl.ac.uk.
¹⁴ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.. Electronic address: f.a.edwards@ucl.ac.uk.

Abstract

Background: Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APP_Swe/PSEN1_M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes.

Methods: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze.

Findings: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours.

Interpretation: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition.

Funding: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC.

Keywords: Alzheimer's disease; Dementia; Microglia; Mouse model; Neurodegeneration; Plaque; Synaptic transmission.

MeSH terms

Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / genetics*
Animals
Behavior, Animal
Cognition / physiology*
Disease Models, Animal
Hemizygote
Hippocampus / metabolism
Hippocampus / physiology*
Humans
Male
Maze Learning
Mice
Mice, Transgenic
Microglia / metabolism
Microglia / physiology*
Presenilin-1 / genetics*
Synaptic Transmission

Substances

APP protein, human
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
PSEN1 protein, human
Presenilin-1

Grants and funding

MR/J011851/1/MRC_/Medical Research Council/United Kingdom