Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice

Journal of Neuroinflammation

Tony Wyss-Coray²  Eliezer Masliah³  Hudson Johns¹  Edward Rockenstein³  Yoshiko Takeda-Uchimura¹  Markus Britschgi¹ 

[1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 1201 Welch Road; MSLS Bldg, Rm P208, Stanford, CA 94305-5489, USA;Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA;Departments of Neurosciences and Pathology, University of California San Diego, 9500 Gilman Drive # 9127, La Jolla, CA 92093-9127, USA

关键词: Tauopathy;    Mouse models of tau pathology;    Innate immune system;    Frontotemporal lobar degeneration;    Complement system;    Alzheimer’s disease;    Age-related neurodegeneration;   

Others  :  1160243
DOI  :  10.1186/1742-2094-9-220

 received in 2012-05-03, accepted in 2012-09-08,  发布年份 2012

【 摘 要 】

Background

The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology.

Findings

We tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry) reduced the number of phospho-tau (AT8 epitope) positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line). CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a−/− mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity.

Conclusions

Our data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.

【 授权许可】

   
2012 Britschgi et al.; licensee BioMed Central Ltd.

【 图 表 】

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