Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies

Janna van Wetering, Hanne Geut, John J. Bol, Yvon Galis, Evelien Timmermans, Jos W.R. Twisk, Dagmar H. Hepp, Martino L. Morella, Lasse Pihlstrom, Afina W. Lemstra, Annemieke J.M. Rozemuller, Laura E. Jonkman, Wilma D.J. van de Berg

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Neuroinflammation and Alzheimer’s disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology. Methods: The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis. Results: Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases. Conclusions: In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

Original languageEnglish
Article number73
JournalActa Neuropathologica Communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2024

Keywords

  • Alpha-synuclein
  • Alzheimer’s disease
  • Amyloid-beta
  • Astroglia
  • Co-pathology
  • Dementia with Lewy bodies
  • Immunohistochemistry
  • Lewy body disease
  • Microglia
  • Neuroinflammation
  • Phosphorylated-tau
  • Post-mortem

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