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Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.

ABSTRACT: Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.

SUBMITTER: Maphis N

PROVIDER: S-EPMC4542622 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.

Maphis Nicole N Xu Guixiang G Kokiko-Cochran Olga N ON Jiang Shanya S Cardona Astrid A Ransohoff Richard M RM Lamb Bruce T BT Bhaskar Kiran K

Brain : a journal of neurology 20150331 Pt 6

Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial a ...[more]

PMID: 25833819

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Project description:Alzheimer's disease is characterized by cortical atrophy on MRI and abnormal depositions of amyloid-beta, phosphorylated-tau and inflammation pathologically. However, the relative contribution of these pathological hallmarks to cortical atrophy, a widely used MRI biomarker in Alzheimer's disease, is yet to be defined. Therefore, the aim of this study was to identify the histopathological correlates of MRI cortical atrophy in Alzheimer's disease donors, and its typical amnestic and atypical non-amnestic phenotypes. Nineteen Alzheimer's disease (of which 10 typical and 9 atypical) and 10 non-neurological control brain donors underwent post-mortem in situ 3T 3D-T1, from which cortical thickness was calculated with Freesurfer. Upon subsequent autopsy, 12 cortical brain regions from the right hemisphere and 9 from the left hemisphere were dissected and immunostained for amyloid-beta, phosphorylated-tau and reactive microglia, and percentage area load was calculated for each marker using ImageJ. In addition, post-mortem MRI was compared to ante-mortem MRI of the same Alzheimer's disease donors when available. MRI-pathology associations were assessed using linear mixed models. Higher amyloid-beta load weakly correlated with higher cortical thickness globally (r = 0.22, P = 0.022). Phosphorylated-tau strongly correlated with cortical atrophy in temporal and frontal regions (-0.76 < r < -1.00, all P < 0.05). Reactive microglia load strongly correlated with cortical atrophy in the parietal region (r = -0.94, P < 0.001). Moreover, post-mortem MRI scans showed high concordance with ante-mortem scans acquired <1 year before death. In conclusion, distinct histopathological markers differently correlated with cortical atrophy, highlighting their different roles in the neurodegenerative process, and therefore contributing to the understanding of the pathological underpinnings of MRI atrophic patterns in Alzheimer's disease. In our cohort, no or only subtle differences were found in MRI-pathology associations in Alzheimer's disease phenotypes, indicating that the histopathological correlates of cortical atrophy in typical and atypical phenotypes might be similar. Moreover, we show that post-mortem in situ MRI can be used as proxy for ante-mortem in vivo MRI.

Project description:Accumulating evidence suggests that misfolded MAPT (microtubule associated protein tau), the main component of neurofibrillary tangles in tauopathies, is subject to degradation by the autophagy-lysosomal pathway. Selective autophagy is a subtype of macroautophagy that requires cargo receptors, such as OPTN (optineurin) or SQSTM1, to recognize specific targets for their sequestration within the autophagosome and their eventual degradation by the lysosome, although their roles in targeting distinct MAPT species have not been fully investigated. Using cargo receptor knockout cell lines and a seeding-based cellular assay in which neurofibrillary tangle pathology can be modeled in vitro, we reveal that while OPTN primarily targets soluble MAPT expressed in physiological conditions, SQSTM1 predominantly degrades insoluble but not soluble mutant MAPT. Endogenous SQSTM1 colocalizes with misfolded and aggregated MAPT species in vitro and in vivo, and both this colocalization and its function in MAPT clearance require both the LC3-interacting region (LIR) motif and also the PB1 self-polymerization domain of SQSTM1. Further, pathogenic MAPT accumulation reduces basal macroautophagy/autophagy in vitro and is associated with a compensatory upregulation of the lysosomal pathway in vivo. Finally, increased expression of SQSTM1 in MAPT transgenic mouse brains ameliorates MAPT pathology and prion-like spreading. Our results uncover distinct properties of selective autophagy receptors in targeting different MAPT species, implicate compromised autophagy as a potential underlying factor in mutant MAPT deposition, and demonstrate a potent and specific role of SQSTM1 in targeted clearance of pathogenic MAPT, through which it blocks neurofibrillary tangle accumulation and pathological spreading. Abbreviations: AAV: adeno-associated virus; AD: Alzheimer disease; ALP: autophagy-lysosomal pathway; ALS: amyotrophic lateral sclerosis; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; FTD: frontotemporal dementias; HD: Huntington disease; HTT: huntingtin; LIR: LC3-interacting region; NBR1: autophagy cargo receptor; NFE2L2/Nrf2: nuclear factor, erythroid derived 2, like 2; NFTs: neurofibrillary tangles; MAPT: microtubule associated protein tau; OPTN: optineurin; p-MAPT: hyperphosphorylated MAPT; PFA: paraformaldehyde; TARDBP/TDP-43: TAR DNA binding protein; TAX1BP1 Tax1: binding protein 1; ThioS: thioflavin-S; UBA: ubiquitin-associated.

Dataset Information

Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.

Publications

Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.

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