Soluble Conformers of Aβ and Tau Alter Selective Proteins Governing Axonal Transport
| العنوان: | Soluble Conformers of Aβ and Tau Alter Selective Proteins Governing Axonal Transport |
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| المؤلفون: | Mathew A. Sherman, Adriano Aguzzi, Megan Larson, Colleen L. Forster, David A. Bennett, Sylvain Lesné, Michael LaCroix, Martin Ramsden, Fatou Amar |
| المصدر: | The Journal of Neuroscience. 36:9647-9658 |
| بيانات النشر: | Society for Neuroscience, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adult, 0301 basic medicine, Protein Conformation, Amyloid beta, Kinesins, Mice, Transgenic, tau Proteins, Axonal Transport, Amyloid beta-Protein Precursor, Mice, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, mental disorders, medicine, Animals, Humans, education, Cells, Cultured, Neurons, education.field_of_study, Amyloid beta-Peptides, biology, Chemistry, General Neuroscience, Neurodegeneration, Age Factors, Brain, Neurofibrillary Tangles, Neurofibrillary tangle, Articles, Human brain, Embryo, Mammalian, medicine.disease, Anterograde axonal transport, Cell biology, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Biochemistry, Kinesin light chain 1, Mutation, biology.protein, Axoplasmic transport, Microtubule-Associated Proteins, 030217 neurology & neurosurgery, Intracellular |
| الوصف: | Despite the demonstration that amyloid-β (Aβ) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formationin vivo, the molecular link associating Aβ and tau pathologies remains ill defined. Here, we observed that exposure of cultured primary neurons to Aβ trimers isolated from brain tissue of subjects with Alzheimer's disease led to a specific conformational change of tau detected by the antibody Alz50. A similar association was supported by postmortem human brain analyses. To study the role of Aβ trimersin vivo, we created a novel bigenic Tg-Aβ+Tau mouse line by crossing Tg2576 (Tg-Aβ) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent Aβ trimers were increased by ∼2-fold in 3-month-old Tg-Aβ and Tg-Aβ+Tau mice compared with younger mice, whereas soluble monomeric Aβ levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ∼2.2-fold in the forebrains of Tg-Aβ+Tau mice compared with nontransgenic littermates. In parallel, APP accumulated intracellularly, suggestive of a putative dysfunction of anterograde axonal transport. We found that the protein abundance of the kinesin-1 light chain (KLC1) was reduced selectivelyin vivoandin vitrowhen soluble Aβ trimers/Alz50-tau were present. Importantly, the reduction in KLC1 was prevented by the intraneuronal delivery of Alz50 antibodies. Collectively, our findings reveal that specific soluble conformers of Aβ and tau cooperatively disrupt axonal transport independently from plaques and tangles. Finally, these results suggest that not all endogenous Aβ oligomers trigger the same deleterious changes and that the role of each assembly should be considered separately.SIGNIFICANCE STATEMENTThe mechanistic link between amyloid-β (Aβ) and tau, the two major proteins composing the neuropathological lesions detected in brain tissue of Alzheimer's disease subjects, remains unclear. Here, we report that the trimeric Aβ species induce a pathological modification of tau in cultured neurons and in bigenic mice expressing Aβ and human tau. This linkage was also observed in postmortem brain tissue from subjects with mild cognitive impairment, when Aβ trimers are abundant. Further, this modification of tau was associated with the intracellular accumulation of the precursor protein of Aβ, APP, as a result of the selective decrease in kinesin light chain 1 expression. Our findings suggest that Aβ trimers might cause axonal transport deficits in AD. |
| تدمد: | 1529-2401 0270-6474 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d33855c5746459f4ecdbd6e76ac61e84Test https://doi.org/10.1523/jneurosci.1899-16.2016Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d33855c5746459f4ecdbd6e76ac61e84 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15292401 02706474 |
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