Tau, a neuronal microtubule-associated protein that aggregates in Alzheimer disease is a natively unfolded protein. In solution, Tau adopts a "paperclip" conformation, whereby the N- and C-terminal domains approach each other and the repeat domain ( Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H. J., and Mandelkow, E. (2006) Biochemistry 45, 2283-2293 ). In AD, Tau is in a hyperphosphorylated state. The consequences for microtubule binding or aggregation are a matter of debate. We therefore tested whether phosphorylation alters the conformation of Tau. To avoid the ambiguities of heterogeneous phosphorylation we cloned "pseudo-phosphorylation" mutants of Tau where combinations of Ser or Thr residues were converted into Glu. These mutations were combined with FRET pairs inserted in different locations to allow distance measurements. The results show that the paperclip conformation becomes tighter or looser, depending on the pseudo-phosphorylation state. In particular, pseudo-phosphorylation at the epitope of the diagnostic antibody AT8* (S199E + S202E + T205E) moves the N-terminal domain away from the C-terminal domain. Pseudo-phosphorylation at the PHF1 epitope (S396E + S404E) moves the C-terminal domain away from the repeat domain. In both cases the paperclip conformation is opened up. By contrast, the combination of AT8* and PHF1 sites leads to compaction of the paperclip, such that the N-terminus approaches the repeat domain. The compaction becomes even stronger by combining pseudo-phosphorylated AT8*, AT100, and PHF1 epitopes. This is accompanied by a strong increase in the reaction with conformation-dependent antibody MC1, suggesting the generation of a pathological conformation characteristic for Tau in AD. Furthermore, the compact paperclip conformation enhances the aggregation to paired helical filaments but has little influence on microtubule interactions. The data provide a framework for the global folding of Tau dependent on proline-directed phosphorylation in the domains flanking the repeats and the consequences for pathological properties of Tau.

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

The Alzheimer’s disease (AD) therapeutic research is yielding a large number of potent molecules. The nanoparticle-based therapeutics against the protein aggregation in AD is also taking a lead especially with amyloid-β as a primary target. In this work, we have screened for the first time protein-capped (PC) metal nanoparticles for their potency in inhibiting Tau aggregation in vitro. We present a novel function of PC-Fe₃O₄ and PC-CdS nanoparticles as potent Tau aggregation inhibitors by fluorescence spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and electron microscopy. We demonstrate that the biologically synthesized PC-metal nanoparticles, especially iron oxide do not affect the viability of neuroblastoma cells. Moreover, PC-CdS nanoparticles show dual properties of inhibition and disaggregation of Tau. Thus, the nanoparticles can take a lead as potent Tau aggregation inhibitors and can be modified for specific drug delivery due to their very small size. The current work presents unprecedented strategy to design anti-Tau aggregation drugs, which provides interesting insights to understand the role of biological nanostructures in Alzheimer’s disease.