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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-06-10

AUTHORS

Wolfgang J. Streit, Heiko Braak, Qing-Shan Xue, Ingo Bechmann

ABSTRACT

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. More... »

PAGES

475-485

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00401-009-0556-6

DOI

http://dx.doi.org/10.1007/s00401-009-0556-6

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1039635119

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19513731


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113 neuropathology
114 neuroprotection
115 notion
116 onset
117 order
118 pathogenesis
119 pathology
120 patients
121 presence
122 protein
123 purpose
124 questions
125 recent work
126 resolution
127 results
128 role
129 severe AD pathology
130 sites
131 situ
132 spectra
133 sporadic AD
134 sporadic Alzheimer's disease
135 spread
136 staging
137 structure
138 study
139 syndrome
140 system insult
141 systemic infectious disease
142 tau
143 tau pathology
144 tau-positive structures
145 terms
146 treatment approaches
147 vicinity
148 view
149 work
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