Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice
Year: 2012
Type: article
Abstract: 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.
Source: Journal of Neuroinflammation
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,090
Awards: Gene Therapy for Alzheimer's Disease, How are complement receptors involved in the clearance of beta-amyloid peptide and reduction of neurodegeneration?-Studies in transgenic mouse models with Alzheimer's disease-type pathology, a-synuclein clearance strategies for the treatment of Lewy body disease, TGFbeta signaling in neurodegeneration and Alzhimer's, Controlled Activation of Complement to Treat Alzheimer's, G486772123, G6453708846, G9000035899, G9000191018
OpenAlex ID: W2119948079