Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice
© Britschgi et al.; licensee BioMed Central Ltd. 2012
Received: 3 May 2012
Accepted: 8 September 2012
Published: 18 September 2012
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.
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.
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.
KeywordsAge-related neurodegeneration Alzheimer’s disease Complement system Frontotemporal lobar degeneration Innate immune system Mouse models of tau pathology Tauopathy
Intraneuronal insoluble deposits of the microtubule-associated protein tau are found in neurodegenerative diseases commonly known as tauopathies . One of the causes leading to these deposits in sporadic tauopathies may be aberrant phosphorylation of tau. A common feature in Alzheimer’s disease (AD), the most prevalent tauopathy, and other tauopathies is activation of immune pathways in the brain. The complement system is a key innate immune pathway, which is fully expressed in the brain, independent of peripheral contribution, and exerts critical homeostatic cerebral functions in development and aging (for extensive discussions and citations of relevant original articles about the role of complement system in the brain see [2, 3]). Brains of patients with Pick’s disease (a pure tauopathy), AD, or individuals with Down’s syndrome with AD-pathology are found to have tangle-bearing neurons that are decorated with complement proteins, including the membrane attack complex (MAC). The presence of MAC in the brain even at early stages of AD or the deposition of products of complement activation in aged normal brains  suggests a lack of proper inhibitory control of the cascade with age and disease. Indeed, in affected brain regions of AD patients, levels of the main inhibitor of the MAC, CD59, are reduced [5, 6]. These histological and biochemical findings in human beings open the question whether complement activation and formation of the MAC, in particular, are involved in the development of tau pathology.
Earlier studies in mouse models of tauopathies reported a strong link between microglia activation and development of tau pathology [13–17] or vice versa . Whereas some identified this link after administration of an exogenous trigger of inflammation [14–16], we observed a significant correlation between microglial activation and the number of AT8-positive cells in tau transgenic mice in the absence of exogenous stimuli (Figure 1D,E), which is consistent with findings in the brains of AD patients .
A growing number of studies show that the complement system probably has multiple functions in normal and injured brain and this may be relevant for AD [2, 3]. For instance, overexpression of sCrry or ablating C3 in APP transgenic mouse models of AD accelerated formation of amyloid-β plaques and neurodegeneration [20, 21]. This apparently protective effector function of the central component of the complement cascade may involve the opsonization of plaques followed by clearance of amyloid (Figure 1A). In contrast, full activation of the complement system and the terminal or lytic pathway can lead to formation of the MAC with possibly detrimental consequences. If not properly controlled by CD59, the MAC can generate differently sized (lytic and sublytic) pores in the cell membrane. Such pores then lead to increased Ca2+ influx, which may trigger depolarization of the membrane and activation of kinases in the cell . Thus, full complement activation involving the terminal pathway and MAC formation may be upstream in the activation of kinases, such as MAPK, PKC, JNK, or PI3K/AKT, which have been implicated in the regulation of tau phosphorylation. Cellular and in vivo experiments also demonstrate that MAC formation in neurons can induce seizures and excitotoxicity, which promote neurodegeneration . Excitotoxicity and seizures have also been proposed to contribute to cognitive decline in AD mouse models and patients. Interestingly, the absence of tau protects APP transgenic and wild-type mice from excitotoxic insults and prevents behavioral deficits . Whether MAC formation and excitotoxicity are linked through tau would need to be studied in more detail.
Neuropathological analyses in human beings and our in vivo data do indeed point to an active role of the terminal complement pathway in the development of tau pathology, a neuropathological hallmark of AD and other tauopathies. Intriguingly, recent genome-wide association studies identified independently genetic variants of complement receptor 1 (CR1/CD35) and clusterin to be associated with AD (, replicated by others: http://www.alzgene.org). CR1/CD35 is one of the human functional analogs of the murine Crry and clusterin, which is also known as apolipoprotein J or complement lysis inhibitor, acts just one step upstream of CD59. It is interesting that, out of all immune-function-related proteins, two key regulators of the central component and the terminal cascade seem to be genetically linked with AD. It remains to be shown whether variants of genes coding for complement components or regulators are associated with other tauopathies as well.
In summary, complement proteins are key components of the innate immune system and have been implicated in homeostasis as well as degeneration of the human brain. Our data in two independent mouse models with genetic alterations in complement regulatory proteins 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 and, more specifically, inhibition of the MAC may be beneficial in tauopathies.
Adeno-associated virus serotype 2
Complement receptor 1
Green fluorescent protein
Membrane attack complex
Microtubule-associated protein 2
Soluble complement receptor 1-related gene/protein y
We thank Drs. S. Tomlinson (Medical University of South Carolina, USA) and BP Morgan (Cardiff University School of Medicine, UK) for providing the Cd59a−/− mice, and J Warner and LH Mondshein for technical assistance. This work was supported by the Swiss National Science Foundation (postdoctoral fellowship PBBEB-102096 to MB), NIH (AG18440, AG02074, AG10435 to EM), National Institute on Aging (AG20603 and AG27505 to TW-C), and the Department of Veterans Affairs (TW-C).
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