Dataset Information

Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy.

ABSTRACT: Neurofibrillary tangles (NFTs) have been implicated in mediating neuronal death and disease progression in human tauopathies; however, mounting in vivo data suggest that NFTs may not be the primary initiators of neurotoxicity. Caspase activity has been implicated in processes associated with the development of tauopathy, but the position that caspase activation holds in neurodegenerative cascades remains uncertain. Using multiphoton real-time imaging microscopy, de Calignon et al recently demonstrated that caspase activation precedes and leads to tangle formation within 24 hours in the rTg4510 mouse model of tauopathy. Here, we used immunoelectron microscopy to determine whether caspase-cleaved tau was present in NFTs of rTg4510 mice. Using a caspase-cleaved tau-specific antibody (TauC3), we found very little immunogold labeling in NFTs in the brains of rTg4510 mice. By immunohistochemistry, the number of TauC3-positive neurons was far less than the numbers of neurons stained with the MC1 antibody, which recognizes abnormal conformations of tau. Biochemically, caspase-cleaved tau was barely detectable in fractions of rTg4510 mouse brain extracts. Our data suggest that caspase activation might be one of multiple routes through which NFT formation occurs, rather than an obligatory initiation step in pathologic tau production in rTg4510 mice.

SUBMITTER: Lin WL

PROVIDER: S-EPMC3162471 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy.

Lin Wen-Lang WL Dickson Dennis W DW Sahara Naruhiko N

Journal of neuropathology and experimental neurology 20110901 9

Neurofibrillary tangles (NFTs) have been implicated in mediating neuronal death and disease progression in human tauopathies; however, mounting in vivo data suggest that NFTs may not be the primary initiators of neurotoxicity. Caspase activity has been implicated in processes associated with the development of tauopathy, but the position that caspase activation holds in neurodegenerative cascades remains uncertain. Using multiphoton real-time imaging microscopy, de Calignon et al recently demons ...[more]

PMID: 21865886

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Project description:APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Project description:Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2-25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3-25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3-25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

Dataset Information

Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy.

Publications

Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy.

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