Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease

By Wolfgang Streit, H. Braak, Qing-Shan Xue, I. Bechmann. Acta Neuropathologica, 2009

695 citations recorded by the source corpus.

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 (Aβ) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Aβ 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.

Subfields: Neurology, Physiology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/266552504f23dadc9fe555e1b0c00e01006da286

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Citations in the corpus

Microglia: biology and pathology (2009, background): “These findings argue strongly against the hypothesis that neuroinflammatory changes contribute to AD dementia [171] but do not exclude interactions between microglia and betaamyloid deposits.”
Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond (2009, background): “First, for infection, as in the recent outbreak of bovine spongiform encephalopathy in Britain or the current epidemic of prionmediated wasting disease in American deer (Tamgüney et al., 2009), an initial noncell-autonomous contribution is after ingestion of prions.”
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases (2015, background): “In the aged brain, many microglia cells undergo various molecular and cellular changes and even morphological features indicative of senescence, such as fragmented cytoplasmic processes, rendering them lose the ability to protect the brain [144, 145].”
The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases (2017, background): “In a mouse model and in human AD, neuritic Ab-plaque-associated microglia showed a MGnD phenotype consistent with reports of senescent microglia in aging and AD (Streit et al., 2009).”
Microglia in Alzheimer’s disease (2018, background): “Relative to the most common apoE3 variant, a single apoE4 or apoE2 allele confers an approximately threefold increased or approximately twofold reduced risk of developing AD, respectively (Corder et al., 1993, 1994; Strittmatter et al., 1993; Farrer et al., 1997).”
High‐Dimensional Single‐Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease (2018, neutral): “Aging is a major risk factor for neurodegenerative diseases, and changes in microglial morphology precede pathology in Alzheimer’s patients (Perry and Holmes, 2014; Streit et al., 2009).”