Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model

Yoshiyama, Yasumasa; Higuchi, Makoto; Zhang, Bin; Huang, Shu-Ming; Iwata, Nobuhisa; Saido, Takaomi C.; Maeda, Jun; Suhara, Tetsuya; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1016/j.neuron.2007.03.022

Cited by 377 publications

(676 citation statements)

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“…such as cyclosporine and FK-506 (tacrolimus), can revert these A␤-related pathological changes both in vitro and in vivo and ameliorate both the neuropathological features and the memory deficits of AD mouse models. 26,[51][52][53] In summary, our findings indicate a major role of gliosis in the pathophysiological features of both amyloid plaques and NFTs, suggesting that glial cells might be proactive players linking A␤ with downstream neurodegenerative events beyond their role in the initial steps of the amyloid cascade. The implications of these results for the development of imaging biomarkers and diseasemodifying drugs encourage further research.…”

Section: Diagnostic and Therapeutic Implicationsmentioning

confidence: 66%

“…19 In addition, recent experimental studies with in vitro and mouse models of AD have linked both astrocytes and microglia to neurodegeneration 20 -25 and have shown that activated microglia can lead to hyperphosphorylation and aggregation. 26,27 The idea of reactive glia as a hostile environment for neurons in the context of neurodegeneration has been recently proposed by elegant studies 28,29 on amyotrophic lateral sclerosis and tauopathy mouse models. If this idea proves to apply to AD, an increasing number of reactive glial cells around dense-core plaques might well contribute to their local toxicity by releasing soluble biologically active toxic molecules, such as pro-inflammatory cytokines and reactive oxygen species.…”

Section: Implications For the Role Of Reactive Glial Cells In Admentioning

confidence: 99%

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Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

Serrano-Pozo

Mielke

Gómez-Isla

et al. 2011

The American Journal of Pathology

382

331

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Senile plaques are a prominent pathological feature of Alzheimer's disease (AD), but little is understood about the association of glial cells with plaques or about the dynamics of glial responses through the disease course. We investigated the progression of reactive glial cells and their relationship with AD pathological hallmarks to test whether glial cells are linked only to amyloid deposits or also to tangle deposition, thus integrating both lesions as a marker of disease severity. We conducted a quantitative stereology-based post-mortem study on the temporal neocortex of 15 control subjects without dementia and 91 patients with AD, including measures of amyloid load, neurofibrillary tangles, reactive astrocytes, and activated microglia. We also addressed the progression of glial responses in the vicinity (<50 m) of dense-core plaques and tangles. Although the amyloid load reached a plateau early after symptom onset, astrocytosis and microgliosis increased linearly throughout the disease course. Moreover, glial responses correlated positively with tangle burden, whereas astrocytosis correlated negatively with cortical thickness. However, neither correlated with amyloid load. Glial responses increased linearly around existing plaques and in the vicinity of tangles. These results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques. They also suggest that reactive glia might contribute to the ongoing neurodegeneration.

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Section: Diagnostic and Therapeutic Implicationsmentioning

confidence: 66%

Section: Implications For the Role Of Reactive Glial Cells In Admentioning

confidence: 99%

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

Serrano-Pozo

Mielke

Gómez-Isla

et al. 2011

The American Journal of Pathology

382

331

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“…Activated microglia can also exacerbate tau pathology (Kitazawa et al, 2005;Li et al, 2003;Yoshiyama et al, 2007) through a mechanism dependent on the cdk5/p25 (Kitazawa et al, 2005) (Fig. 2).…”

Section: Inflammation In Neurodegenerative Disordersmentioning

confidence: 99%

“…Chronic microglial activation contributes to neurodegenerative events such as plaque formation, dystrophic neurite growth and tau hyperphosphorylation. A recent study in a P301S tauopathy mouse model describes synaptic loss and microglial activation preceding tangle formation (Yoshiyama et al, 2007). Thus, microglia driven neuropathological responses constitute itself a pathogenic factor in neurodegenerative diseases such as AD.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

Conejero-Goldberg

Davies

Ulloa

2008

Neuroscience & Biobehavioral Reviews

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Alzheimer's disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders.

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“…Indeed, recent studies in tau Tg mice showed that treating these mice with the immunosupressant FK506 before disease onset had a dramatic effect on the tau pathology and 60% of FK506-treated animals survived to one year compared to only 20% of untreated mice [18]. Some of the treated mice had very little tau pathology and no overt hippocampal atrophy even several months after the development of tau tangles in untreated mice.…”

Section: Neuroprotective Therapies For Ftdsmentioning

confidence: 99%

New directions for frontotemporal dementia drug discovery

Trojanowski

Duff

Fillit

et al. 2007

Alzheimer's & Dementia

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This report summarizes the recommendations of the Frontotemporal Dementia (FTD) Working Group on FTD Drug Discovery that was part of an international FTD Workshop held in January 18th and 19th, 2007 in Miami, Florida. The workshop was sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) of the National Institutes of Health (NIH) and the Association for Frontotemporal Dementia (AFTD) with the express purpose of defining opportunities to improve the diagnosis and treatment of patients affected by a neurodegenerative disorder classified as one of the many variants of FTD. Recognition that almost all forms of FTD are due to TDP-43 proteinopathies and tauopathies creates new opportunities for FTD drug discovery targeting pathways of TDP-43 and tau mediated neurodegeneration as reviewed here.

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Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model

Abstract: In Figure 7 on page 345, the image in panel (E) (6-month-old nTg) is repeated in panel (F) instead of showing 1-month-old PS19. Figure 7F should have been replaced by the version shown below. Figure 7F.

Cited by 377 publications

References 0 publications

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

New directions for frontotemporal dementia drug discovery

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