Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R p -adenosine 3 ,5 -cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

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Although interlayer binding energy (IBE) is a key parameter relevant to the electronic properties and device performances of hexagonal MoS 2 , a promising two-dimensional (2D) semiconductor, it has never been determined experimentally. Herein, we report a novel peeling-to-fracture method for measuring the interlayer binding energy of a two-dimensional hexagonal MoS 2 . In the method, a few upper layers of a multilayer MoS 2 nanoflake are in situ radially peeled off to form a circular truncated cone by lifting up a metal disk deposited on it in a scanning electron microscope (SEM), until the peeled layers fracture at the perimeter of the metal disk. By analyzing the peeling-to-fracture process using a continuum mechanical model, the interlayer binding energy of MoS 2 is obtained in terms of its Young's modulus, fracture strength, and geometric parameters of the circular truncated cone. By employing well-determined Young's modulus and fracture strength of hexagonal MoS 2 from previous literatures, the interlayer binding energy of a mechanically exfoliated MoS 2 is determined to be 0.55 ± 0.13 J m −2 . The interlayer binding energy of hexagonal MoS 2 is calculated to be about 0.422 J m −2 by density function theory calculations. Our results give a quantitative knowledge of the van der Waals interlayer interactions of hexagonal MoS 2 and provide a general method for measuring the interlayer binding energy of two-dimensional materials.

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The flexible and clinging nature of ultrathin films requires an understanding of their elastic and adhesive properties in a wide range of circumstances from fabrications to applications. Simultaneously measuring both properties, however, is extremely difficult as the film thickness diminishes to the nanoscale. Here we address such difficulties through peeling by pulling thin films off from the substrates (we thus refer to it as “pull-to-peel”). Particularly, we perform in situ pull-to-peel of graphene and MoS2 films in a scanning electron microscope and achieve simultaneous determination of their Young’s moduli and adhesions to gold substrates. This is in striking contrast to other conceptually similar tests available in the literature, including indentation tests (only measuring elasticity) and spontaneous blisters (only measuring adhesion). Furthermore, we show a weakly nonlinear Hooke’s relation for the pull-to-peel response of two-dimensional materials, which may be harnessed for the design of nanoscale force sensors or exploited in other thin-film systems.