Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease
Open accessAbstract
The role of microglial cells in the pathogenesis of Alzheimer's disease (AD) neurodegeneration is unknown. Although several works suggest that chronic neuroinflammation caused by activated microglia contributes to neurofibrillary degeneration, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology. This raises the question if indeed microglial activation occurs in the human brain at sites of neurofibrillary degeneration. In view of the recent work demonstrating presence of dystrophic (senescent) microglia in aged human brain, the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. We used a newly optimized immunohistochemical method for visualizing microglial cells in human archival brain together with Braak staging of neurofibrillary pathology to ascertain the morphology of microglia in the vicinity of tau-positive structures. We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down's syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Abeta) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Abeta does not trigger microglial activation. Our findings also indicate that when microglial activation does occur in the absence of an identifiable acute central nervous system insult, it is likely to be the result of systemic infectious disease. The findings reported here strongly argue against the hypothesis that neuroinflammatory changes contribute to AD dementia. Instead, they offer an alternative hypothesis of AD pathogenesis that takes into consideration: (1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, sporadic AD is inextricably linked to aging. They support the idea that progressive, aging-related microglial degeneration and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic Alzheimer's disease. The results have far-reaching implications in terms of reevaluating current treatment approaches towards AD.
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Iba1 is a pan-microglial marker whose expression increases with microglial activation.
“Iba1 is a pan-microglial marker whose expression increases with microglial activation,58, 77”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [77]
The Results (Fig. 1; page unavailable) say anti-Iba1 labeled the entire microglial population, supporting its use as a pan-microglial marker. The Results and Discussion distinguish activated cells by hypertrophy and morphology, but do not say that Iba1 expression increases with activation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDystrophic microglia, much more than activated microglia, are present in human Alzheimer's disease.
“In fact, we have shown that dystrophic, much more than activated microglia are present in human AD [83,104,107].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [83]
Studies using cell counting for Iba1 assess the absolute number of microglia in the samples.
“In contrast, the studies using cell counting for Iba1, which is expressed by all microglia,58, 77 assess the absolute number of microglia in the samples.”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [77]
With ageing, microglial cells exhibit dystrophic changes, which are thought to be distinct from their typical reactive morphology.
“With ageing, microglial cells exhibit dystrophic changes, which are thought to be distinct from their typical reactive morphology.”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [157]
Neuropathological features of AD are associated with dystrophic microglial cells that exhibit morphological changes indicative of senescence.
“neuropathological features of AD have been associated with dystrophic microglial cells that exhibit morphological changes indicative of senescence [157].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [157]
Human AD involves impairments in microglial activation.
“genetic and histological findings suggest that human AD involves impairments in microglial activation (Hansen et al., 2018; Streit et al., 2009).”
From Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation (2020) · cites this paper as Streit et al., 2009
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“, human iPSC-derived microglia), given some reports that indicate differences in microglia responses between humans and mice (Streit et al., 2009; Navarro et al., 2018; Streit et al., 2018; Olah et al., 2020).”
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“However, microglia display a broad spectrum of morphologies, ranging from hyper-ramified forms in response to stress [88], to senescent, dark and dystrophic phenotypes in stress, aging and disease [28, 77, 89, 90].”
- Authors
- Streit, W. J., Braak, H., Xue, Q.-S., & Bechmann, I.
- Affiliations
- University of Florida Health (US)
- Universität Ulm (DE)
- University Hospital Frankfurt (DE)
- Corresponding author
- Streit, Wolfgang J.
- Venue
- Acta Neuropathologica
- Published
- 2009-06-10
- Volume
- 118
- Issue
- 4
- Pages
- 475-485
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC2737117
- OpenAlex
- W2072210142
- Cited by
- 727
- References
- 47
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 67 · 2023: 49 · 2022: 58 · 2021: 70 · 2020: 64 · 2019: 50 · 2018: 49 · 2017: 33 · 2016: 34 · 2015: 38 · 2014: 31 · 2013: 35 · 2012: 25
- FWCI
- 17.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Acta Neuropathologica (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute on Aging (R01AG023665, AG 023665)
- 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
- Alzheimer's disease, microglial activation, tau pathology, neurofibrillary degeneration, neuroinflammation, amyloid-beta, Braak staging, Down syndrome, sporadic Alzheimer's disease, neuroprotection, aging, neurodegeneration, neuropil threads, neuritic plaques, systemic infection, microglial morphology
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Cerebral Cortex, Down Syndrome, Female, Humans, Immunohistochemistry, Male, Middle Aged, Nerve Degeneration, Neurofibrillary Tangles, tau Proteins, Microglia, Neuropil Threads
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