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

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.

Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer’s Disease and Type 2 Diabetes

“…Likewise, the close relationship between AD and T2D has been long analyzed ( Biessels and Despa, 2018 ; Vieira et al, 2018 ). Studies on animal models have shown that metabolic alterations may affect different amyloid species and amyloid deposition, although the effects seem to be highly dependent on the specific animal model used ( Ramos-Rodriguez et al, 2014 ; Wang et al, 2014 ; Chatterjee and Mudher, 2018 ; Natunen et al, 2020 ). On the other hand, while it is widely accepted that cognitive dysfunction is an important and common comorbidity of diabetes, this effect does not seem to be directly related to alterations in amyloid pathology, and previous studies have reported no differences in cerebrospinal fluid amyloid-β (Aβ)-42 levels, global or regional AD pathology, or amyloid burden ( Arvanitakis et al, 2006 ; Moran et al, 2015 ; Pruzin et al, 2017 ; Biessels and Despa, 2018 ).…”

Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-1

“…Nevertheless, although the pathological significance of serum sTREM2 levels in the continuum of cognitive impairment in type 2 diabetes remains unclear, an in vitro study showed that high levels of glucose activated microglia to up-regulate TREM2 expression and induce an inflammatory response ( 36 ). Furthermore, another study reported that diabetic conditions impaired microglial function in both mice and humans ( 18 ). Hence, as a possibility that serum sTREM2 are derived from adipose tissue ( 19 ) and activated microglia ( 15 ) exists, we speculate that hyperglycemia and/or insulin resistance first triggers the elevation of sTREM2, even in a cognitively normal stage in diabetic conditions, ultimately leading to microglial dysfunction and cognitive impairment if diabetic conditions are not improved.…”

“…Thus, the roles of TREM2 in glucose metabolism remain controversial. Conversely, type 2 diabetes-related metabolic dysfunction altered microglial TREM2 signaling and resulted in microglial dysfunction, which in turn led to cognitive impairment ( 18 ), thereby suggesting pathological implications of TREM2 in the development of diabetes-related cognitive impairment.…”

Soluble TREM2 and Alzheimer-related biomarker trajectories in the blood of diabetic patients based on their cognitive status

“…Another study created a mouse model with both AD-linked genetic backgrounds and the diabetic phenotype. These mice demonstrated impaired microglial responses to AD pathologies, with fewer microglia around Aβ-amyloid plaques and increased number of dystrophic neurites These repressive responses were found to be linked to TREM2-related processes [36]. In addition to these studies in mice, a recent longitudinal study of the DIAN cohort found that faster longitudinal increase in CSF sTREM2 correlated with slower amyloid deposition, slower cortical thinning in the precuneus, and slower decline in cognitive functions in presymptomatic AD-linked mutation carriers [23].…”