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Open Access 01-12-2024 | Alzheimer's Disease | Research

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

Authors: 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

Published in: Acta Neuropathologica Communications | Issue 1/2024

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.

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Title: Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies
Authors: 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
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Pathology
Dementia
Dementia
Published in: Acta Neuropathologica Communications / Issue 1/2024
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-024-01786-z

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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