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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2020

01-12-2020 | Alzheimer's Disease | Research article

Diabetic phenotype in mouse and humans reduces the number of microglia around β-amyloid plaques

Authors: Teemu Natunen, Henna Martiskainen, Mikael Marttinen, Sami Gabbouj, Hennariikka Koivisto, Susanna Kemppainen, Satu Kaipainen, Mari Takalo, Helena Svobodová, Luukas Leppänen, Benjam Kemiläinen, Simo Ryhänen, Teemu Kuulasmaa, Eija Rahunen, Sisko Juutinen, Petra Mäkinen, Pasi Miettinen, Tuomas Rauramaa, Jussi Pihlajamäki, Annakaisa Haapasalo, Ville Leinonen, Heikki Tanila, Mikko Hiltunen

Published in: Molecular Neurodegeneration | Issue 1/2020

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Abstract

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease and type 2 diabetes (T2D) plays an important role in conferring the risk for AD. Although AD and T2D share common features, the common molecular mechanisms underlying these two diseases remain elusive.

Methods

Mice with different AD- and/or tauopathy-linked genetic backgrounds (APPswe/PS1dE9, Tau P301L and APPswe/PS1dE9/Tau P301L) were fed for 6 months with standard diet or typical Western diet (TWD). After behavioral and metabolic assessments of the mice, the effects of TWD on global gene expression as well as dystrophic neurite and microglia pathology were elucidated. Consequently, mechanistic aspects related to autophagy, cell survival, phagocytic uptake as well as Trem2/Dap12 signaling pathway, were assessed in microglia upon modulation of PI3K-Akt signaling. To evaluate whether the mouse model-derived results translate to human patients, the effects of diabetic phenotype on microglial pathology were assessed in cortical biopsies of idiopathic normal pressure hydrocephalus (iNPH) patients encompassing β-amyloid pathology.

Results

TWD led to obesity and diabetic phenotype in all mice regardless of the genetic background. TWD also exacerbated memory and learning impairment in APPswe/PS1dE9 and Tau P301L mice. Gene co-expression network analysis revealed impaired microglial responses to AD-related pathologies in APPswe/PS1dE9 and APPswe/PS1dE9/Tau P301L mice upon TWD, pointing specifically towards aberrant microglial functionality due to altered downstream signaling of Trem2 and PI3K-Akt. Accordingly, fewer microglia, which did not show morphological changes, and increased number of dystrophic neurites around β-amyloid plaques were discovered in the hippocampus of TWD mice. Mechanistic studies in mouse microglia revealed that interference of PI3K-Akt signaling significantly decreased phagocytic uptake and proinflammatory response. Moreover, increased activity of Syk-kinase upon ligand-induced activation of Trem2/Dap12 signaling was detected. Finally, characterization of microglial pathology in cortical biopsies of iNPH patients revealed a significant decrease in the number of microglia per β-amyloid plaque in obese individuals with concomitant T2D as compared to both normal weight and obese individuals without T2D.

Conclusions

Collectively, these results suggest that diabetic phenotype in mice and humans mechanistically associates with abnormally reduced microglial responses to β-amyloid pathology and further suggest that AD and T2D share overlapping pathomechanisms, likely involving altered immune function in the brain.
Appendix
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Metadata
Title
Diabetic phenotype in mouse and humans reduces the number of microglia around β-amyloid plaques
Authors
Teemu Natunen
Henna Martiskainen
Mikael Marttinen
Sami Gabbouj
Hennariikka Koivisto
Susanna Kemppainen
Satu Kaipainen
Mari Takalo
Helena Svobodová
Luukas Leppänen
Benjam Kemiläinen
Simo Ryhänen
Teemu Kuulasmaa
Eija Rahunen
Sisko Juutinen
Petra Mäkinen
Pasi Miettinen
Tuomas Rauramaa
Jussi Pihlajamäki
Annakaisa Haapasalo
Ville Leinonen
Heikki Tanila
Mikko Hiltunen
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2020
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-020-00415-2

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