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Soluble Conformers of A? and Tau Alter Selective Proteins Governing Axonal Transport.


ABSTRACT: UNLABELLED:Despite the demonstration that amyloid-? (A?) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formation in vivo, the molecular link associating A? and tau pathologies remains ill defined. Here, we observed that exposure of cultured primary neurons to A? 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 A? trimers in vivo, we created a novel bigenic Tg-A?+Tau mouse line by crossing Tg2576 (Tg-A?) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent A? trimers were increased by ?2-fold in 3-month-old Tg-A? and Tg-A?+Tau mice compared with younger mice, whereas soluble monomeric A? levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ?2.2-fold in the forebrains of Tg-A?+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 selectively in vivo and in vitro when soluble A? 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 A? and tau cooperatively disrupt axonal transport independently from plaques and tangles. Finally, these results suggest that not all endogenous A? oligomers trigger the same deleterious changes and that the role of each assembly should be considered separately. SIGNIFICANCE STATEMENT:The mechanistic link between amyloid-? (A?) 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 A? species induce a pathological modification of tau in cultured neurons and in bigenic mice expressing A? and human tau. This linkage was also observed in postmortem brain tissue from subjects with mild cognitive impairment, when A? trimers are abundant. Further, this modification of tau was associated with the intracellular accumulation of the precursor protein of A?, APP, as a result of the selective decrease in kinesin light chain 1 expression. Our findings suggest that A? trimers might cause axonal transport deficits in AD.

SUBMITTER: Sherman MA 

PROVIDER: S-EPMC5039246 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Soluble Conformers of Aβ and Tau Alter Selective Proteins Governing Axonal Transport.

Sherman Mathew A MA   LaCroix Michael M   Amar Fatou F   Larson Megan E ME   Forster Colleen C   Aguzzi Adriano A   Bennett David A DA   Ramsden Martin M   Lesné Sylvain E SE  

The Journal of neuroscience : the official journal of the Society for Neuroscience 20160901 37


<h4>Unlabelled</h4>Despite the demonstration that amyloid-β (Aβ) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formation in 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  ...[more]

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