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

Abstract

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␤ϩTau mouse line by crossing Tg2576 (Tg-A␤) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent A␤ trimers were increased by ϳ2-fold in 3-month-old Tg-A␤ and Tg-A␤ϩTau mice compared with younger mice, whereas soluble monomeric A␤ levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ϳ2.2-fold in the forebrains of Tg-A␤ϩTau 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.

The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation

“…In combination with earlier studies (2, 49), these results establish that distinct endogenous Aβ oligomers activate specific neuronal signaling pathways, and that mapping the specific tau changes induced by each of these Aβ toxins might provide a general template for monitoring AD progression. In this context, the recent failures of immunotherapies targeting Aβ in AD might be due to the fact that these antibodies do not bind the correct type of Aβ oligomers or bind specific Aβ oligomers with sufficiently high affinities (70).…”

“…S13). Furthermore we recently reported that Aβ trimers could trigger the formation of Alz50-tau conformers in cultured mouse primary cortical neurons in a selective fashion (49). We therefore measured Alz50-tau abundance in the absence or presence of increasing concentrations of Aβ*56 (0–25 pM), and we failed to observe any changes in Alz50-positive tau conformers.…”

“…We previously showed that tau was hyperphosphorylated at Tyr 18 in neurons treated with these low- n Aβ oligomers whereas p Tyr 18 -Tau abundance was unchanged in the presence of Aβ*56 (2). More recently, we reported that Aβ trimers selectively induced a pathological conformation change of tau detected by the Alz50 antibody in vitro (49). Here we found that Aβ dimers and trimers were not affecting tau phosphorylation at Ser 416 while Aβ*56 triggered a ~2 to 3-fold elevation in pS416-Tau amounts.…”

“…Despite intensive efforts to isolate distinct soluble Aβ species and reporting differential effects of Aβ oligomers purified from human AD brains on neuronal signaling and tau (2, 49), it is also fair to indicate intrinsic limitations of our studies: (1) we cannot exclude the possibility that the relative abundance of these species might be altered ex vivo compared to their endogenous state in vivo due to the absence of Aβ assembly-specific reagents; (2) for the same reason, we can also not rule out the possibility that the conformational state of the purified Aβ species applied onto neurons will be preserved for the duration of the exposure; (3) we cannot assume that the concentrations of Aβ species used in vitro exactly match those found in vivo; related to this point, it is still unclear whether the current ELISA-based approaches can adequately inform on this issue as qualitative differences in Aβ species might be more critical for AD pathophysiology than quantitative differences in total Aβ oligomers (65, 66); (4) the longitudinal profile of distinct Aβ oligomers in aging and in AD is unknown; consequently, the pathophysiological relevance of each separate Aβ assembly, including Aβ*56, in AD requires further confirmation despite independent reports of a potential link between a putative Aβ dodecamer and AD vulnerability in the temporal cortex (18); (5) we cannot exclude the possibility that other forms of Aβ oligomers, not captured by our approach, could affect the Aβ*56-activated NMDAR-CaMKIIα-Tau pathway (67). Clearly, further work is needed to fill these technical and knowledge gaps, but these studies also provide unprecedented insights about differential molecular mechanisms between Aβ oligomers purified from brain tissue.…”

Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ

“…52 Furthermore, Aβ trimers, but not monomers or dimers, have been shown to promote aggregation of the microtubule associated protein tau, which is also involved in the progression Alzheimer’s disease. 53 Although the significance of triangular assemblies of Aβ β-hairpins in Alzheimer’s disease remains to be determined, the results described in this paper further support a model in which trimers are a central feature of Aβ oligomers.…”