Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging
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INTRODUCTION: Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer's disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions. RESULTS: Here we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD + HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer's Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and CD68 (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD + HS-aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB. CONCLUSIONS: We conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes.
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In the hippocampus, six of eight studies identified higher CD68 in Alzheimer's disease and two identified no differences.
“CD68-positive cell counts, staining area or gene expression were measured in the hippocampus in eight studies: six identified higher levels in AD20, 69, 76, 78, 79, 86 and two identified no differences.69, 87”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [69]
The Results section (page unavailable) reports higher CD68 staining in AD than in controls when averaged across hippocampal subregions, supporting this paper’s inclusion among studies finding higher levels. It also reports no significant disease-status effect in some individual regions, but not an overall absence of difference; this paper alone does not establish the six-of-eight and two-of-eight study counts. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBachstetter et al. counted CD68-positive microglia in the hippocampus CA1, CA2/3, CA4 and the dentate gyrus, and noted increases in the CA1 and dentate gyrus relative to controls, but no difference in CA2/3 or CA4.
“For example, Bachstetter et al.69 counted CD68-positive microglia in the hippocampus CA1, CA2/3, CA4 and the dentate gyrus, and noted increases in the CA1 and dentate gyrus relative to controls, but no difference in CA2/3 or CA4.”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [69]
The Results section (page unavailable) reports more CD68-positive staining in CA1 for HS-aging, AD, and AD plus HS-aging than in normal controls, and more staining in the dentate gyrus for AD than in the other groups; it found no significant disease-status effect in CA2/3 or CA4. Those regional comparisons come from staining-positive pixel measurements. The paper also counted large round CD68-positive cells, but the claim conflates those cell counts with the staining results and omits which disease groups showed the increases. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFour studies reported no difference in CD68 in at least one of the brain regions measured.
“and four reported no difference in at least one of the brain regions measured.20, 41, 69, 80”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [69]
Ten studies identified no difference in Iba1 from controls.
“whereas 10 studies identified no difference from controls32, 54, 69, 70, 71, 72, 73, 74, 75, 76”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [69]
iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS.
“In addition to AD GWAS genes, iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS and therefore, can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB in which microglia may play a prominent role (Bachstetter et al., 2015; Crotti et al., 2014; Lui et al., 2016; O’Rourke et al., 2016)(Figure S6C).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Bachstetter et al., 2015
iMGLs can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB.
“In addition to AD GWAS genes, iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS and therefore, can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB in which microglia may play a prominent role (Bachstetter et al., 2015; Crotti et al., 2014; Lui et al., 2016; O’Rourke et al., 2016)(Figure S6C).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Bachstetter et al., 2015
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References 42 · Cited by 258
- Authors
- Bachstetter, A. D., Van Eldik, L. J., Schmitt, F. A., Neltner, J. H., Ighodaro, E. T., Webster, S. J., Patel, E., Abner, E. L., Kryscio, R. J., & Nelson, P. T.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Bachstetter, Adam D.
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2015-05-23
- Volume
- 3
- Issue
- 1
- Pages
- 32-32
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4489160
- OpenAlex
- W2138650666
- Cited by
- 258
- References
- 42
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 21 · 2023: 34 · 2022: 38 · 2021: 36 · 2020: 21 · 2019: 22 · 2018: 23 · 2017: 24 · 2016: 10 · 2015: 2
- FWCI
- 10.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (K99 AG044445)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- hippocampus, Alzheimer's disease, dementia with Lewy bodies, microglial morphology, microglial activation, Iba1, CD68, neuroinflammation, age-related dementia, macrophages
- MeSH terms
- CD68 Molecule, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Autopsy, Calcium-Binding Proteins, Dementia, DNA-Binding Proteins, Female, Hippocampus, Humans, Male, Microfilament Proteins, Sclerosis, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Microglia, Lewy Body Disease
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