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Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
Diabetic phenotype in mouse and humans reduces the number of microglia around β-amyloid plaques
Teemu Natunen1, Henna Martiskainen1, Mikael Marttinen1
1Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
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.
Insights
A Western diet exacerbates Alzheimer's disease (AD) and type 2 diabetes (T2D) pathology by impairing microglial function. This study reveals shared molecular mechanisms linking T2D and AD, highlighting altered brain immune responses.
Area of Science:
- Neuroscience
- Immunology
- Metabolic Disorders
Background:
- Alzheimer's disease (AD) is a leading neurodegenerative disorder, with type 2 diabetes (T2D) significantly increasing its risk.
- Despite shared characteristics, the underlying molecular mechanisms connecting AD and T2D remain largely unknown.
- Investigating these shared pathways is crucial for understanding disease progression and developing targeted therapies.
Purpose of the Study:
- To investigate the impact of a Western diet (TWD) on AD and tauopathy mouse models.
- To elucidate the molecular mechanisms linking T2D and AD, focusing on microglial function.
- To assess the translational relevance of findings in human patient samples.
Main Methods:
- Mice with AD and/or tauopathy genetic backgrounds were fed a standard or Western diet (TWD) for six months.
- Behavioral, metabolic, gene expression, and neuropathological assessments were performed.
- Mechanistic studies in mouse microglia and analysis of human cortical biopsies were conducted.
Main Results:
- TWD induced obesity and diabetic phenotypes in all mice, exacerbating cognitive deficits in AD models.
- TWD impaired microglial responses to AD pathology, linked to altered Trem2/PI3K-Akt signaling, resulting in fewer microglia and more dystrophic neurites.
- Human studies showed reduced microglia per amyloid plaque in obese T2D patients, supporting the mouse model findings.
Conclusions:
- The diabetic phenotype is mechanistically linked to reduced microglial responses to amyloid pathology in both mice and humans.
- AD and T2D share overlapping pathomechanisms, particularly involving dysregulated brain immune function.
- These findings underscore the importance of metabolic health in neurodegenerative disease prevention and treatment.
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