The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress.

The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases.

Sinuous instability of a planar air jet: propagation parameters and acoustic excitation.

The sinuous instability wave of a planar air jet is excited by localized acoustic flow across the nozzle. Phase velocity and the growth exponent are found from synchronous hot-wire measurements made beyond the excited region, where the profile is approximately sech-squared. In the observed range of scaled radian frequency, 0.02-1.33 (the stability limit), results agree with real-frequency (spatially growing) analysis but not with complex-frequency (temporally growing) analysis. The latter predicts smaller phase velocity at low frequencies and has been questioned in edgetone analysis. In further tests, the acoustic driving signal is made independent of downstream distance, as in an organ pipe. The jet deflection is then the sum of acoustic convection and of the instability wave, summing to zero at the nozzle, as proposed by Fletcher, Elder, and others. The instability-wave theory applies to linear behavior in the inviscid limit and therefore to a hypothetical nonspreading jet. The local velocity profile width must be considered in relating to a physical jet. In a flue organ pipe oscillating at equilibrium amplitude the stability-wave theory is not applicable near the lip, where the laminar flow assumed in the theory disappears and the jet deflection exceeds the range of linear behavior. Direct sound generation by the jet is investigated briefly.