Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans.

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with a complex origin, thought to involve a combination of genetic, biological and environmental factors. Insulin dysfunction has emerged as a potential factor contributing to AD pathogenesis, particularly in individuals with diabetes, and among those with insulin deficiency or undergoing insulin therapy. The intraperitoneal administration of streptozotocin (STZ) is widely used in rodent models to explore the impact of insulin deficiency on AD pathology, although prior research predominantly focused on young animals, with no comparative analysis across different age groups. Our study aimed to fill this gap by analyzing the impact of insulin dysfunction in 7 and 23 months 3xTg-AD mice, that exhibit both amyloid and tau pathologies. Our objective was to elucidate the age-specific consequences of insulin deficiency on AD pathology. STZ administration led to insulin deficiency in the younger mice, resulting in an increase in cortical amyloid-ß (Aß) and tau aggregation, while tau phosphorylation was not significantly affected. Conversely, older mice displayed an unexpected resilience to the peripheral metabolic impact of STZ, while exhibiting an increase in both tau phosphorylation and aggregation without significantly affecting amyloid pathology. These changes were paralleled with alterations in signaling pathways involving tau kinases and phosphatases. Several markers of blood-brain barrier (BBB) integrity declined with age in 3xTg-AD mice, which might have facilitated a direct neurotoxic effect of STZ in older mice. Overall, our research confirms the influence of insulin signaling dysfunction on AD pathology, but also advises careful interpretation of data related to STZ-induced effects in older animals.

Temperature-induced Artifacts in Tau Phosphorylation: Implications for Reliable Alzheimer's Disease Research.

In preclinical research on Alzheimer's disease and related tauopathies, tau phosphorylation analysis is routinely employed in both cellular and animal models. However, recognizing the sensitivity of tau phosphorylation to various extrinsic factors, notably temperature, is vital for experimental accuracy. Hypothermia can trigger tau hyperphosphorylation, while hyperthermia leads to its dephosphorylation. Nevertheless, the rapidity of tau phosphorylation in response to unintentional temperature variations remains unknown. In cell cultures, the most significant temperature change occurs when the cells are removed from the incubator before harvesting, and in animal models, during anesthesia prior to euthanasia. In this study, we investigate the kinetics of tau phosphorylation in N2a and SH-SY5Y neuronal cell lines, as well as in mice exposed to anesthesia. We observed changes in tau phosphorylation within the few seconds upon transferring cell cultures from their 37°C incubator to room temperature conditions. However, cells placed directly on ice post-incubation exhibited negligible phosphorylation changes. In vivo, isoflurane anesthesia rapidly resulted in tau hyperphosphorylation within the few seconds needed to lose the pedal withdrawal reflex in mice. These findings emphasize the critical importance of preventing temperature variation in researches focused on tau. To ensure accurate results, we recommend avoiding anesthesia before euthanasia and promptly placing cells on ice after removal from the incubator. By controlling temperature fluctuations, the reliability and validity of tau phosphorylation studies can be significantly enhanced.

Linear-in temperature resistivity from an isotropic Planckian scattering rate.

A variety of 'strange metals' exhibit resistivity that decreases linearly with temperature as the temperature decreases to zero1-3, in contrast to conventional metals where resistivity decreases quadratically with temperature. This linear-in-temperature resistivity has been attributed to charge carriers scattering at a rate given by h/τ = αkBT, where α is a constant of order unity, h is the Planck constant and kB is the Boltzmann constant. This simple relationship between the scattering rate and temperature is observed across a wide variety of materials, suggesting a fundamental upper limit on scattering-the 'Planckian limit'4,5-but little is known about the underlying origins of this limit. Here we report a measurement of the angle-dependent magnetoresistance of La1.6-xNd0.4SrxCuO4-a hole-doped cuprate that shows linear-in-temperature resistivity down to the lowest measured temperatures6. The angle-dependent magnetoresistance shows a well defined Fermi surface that agrees quantitatively with angle-resolved photoemission spectroscopy measurements7 and reveals a linear-in-temperature scattering rate that saturates at the Planckian limit, namely α = 1.2 ± 0.4. Remarkably, we find that this Planckian scattering rate is isotropic, that is, it is independent of direction, in contrast to expectations from 'hotspot' models8,9. Our findings suggest that linear-in-temperature resistivity in strange metals emerges from a momentum-independent inelastic scattering rate that reaches the Planckian limit.

Nernst and Seebeck coefficients of the cuprate superconductor YBa2Cu3O6.67: a study of Fermi surface reconstruction.

The Seebeck and Nernst coefficients S and nu of the cuprate superconductor YBa{2}Cu{3}O{y} (YBCO) were measured in a single crystal with doping p=0.12 in magnetic fields up to H=28 T. Down to T=9 K, nu becomes independent of field by H approximately 30 T, showing that superconducting fluctuations have become negligible. In this field-induced normal state, S/T and nu/T are both large and negative in the T-->0 limit, with the magnitude and sign of S/T consistent with the small electronlike Fermi surface pocket detected previously by quantum oscillations and the Hall effect. The change of sign in S(T) at T approximately 50 K is remarkably similar to that observed in La2-xBaxCuO4, La{2-x-y}Nd{y}Sr_{x}CuO{4}, and La{2-x-y}Eu{y}Sr{x}CuO{4}, where it is clearly associated with the onset of stripe order. We propose that a similar density-wave mechanism causes the Fermi surface reconstruction in YBCO.

Broken rotational symmetry in the pseudogap phase of a high-T(c) superconductor.

The nature of the pseudogap phase is a central problem in the effort to understand the high-transition-temperature (high-T(c)) copper oxide superconductors. A fundamental question is what symmetries are broken when the pseudogap phase sets in, which occurs when the temperature decreases below a value T*. There is evidence from measurements of both polarized neutron diffraction and the polar Kerr effect that time-reversal symmetry is broken, but at temperatures that differ significantly from one another. Broken rotational symmetry was detected from both resistivity measurements and inelastic neutron scattering at low doping, and from scanning tunnelling spectroscopy at low temperature, but showed no clear relation to T*. Here we report the observation of a large in-plane anisotropy of the Nernst effect in YBa(2)Cu(3)O(y) that sets in precisely at T* throughout the doping phase diagram. We show that the CuO chains of the orthorhombic lattice are not responsible for this anisotropy, which is therefore an intrinsic property of the CuO(2) planes. We conclude that the pseudogap phase is an electronic state that strongly breaks four-fold rotational symmetry. This narrows the range of possible states considerably, pointing to stripe or nematic order.

Enhancement of the Nernst effect by stripe order in a high-T(c) superconductor.

The Nernst effect in metals is highly sensitive to two kinds of phase transition: superconductivity and density-wave order. The large, positive Nernst signal observed in hole-doped high-T(c) superconductors above their transition temperature (T(c)) has so far been attributed to fluctuating superconductivity. Here we report that in some of these materials the large Nernst signal is in fact the result of stripe order, a form of spin/charge modulation that causes a reconstruction of the Fermi surface. In La(2-x)Sr(x)CuO(4) (LSCO) doped with Nd or Eu, the onset of stripe order causes the Nernst signal to change from being small and negative to being large and positive, as revealed either by lowering the hole concentration across the quantum critical point in Nd-doped LSCO (refs 6-8) or by lowering the temperature across the ordering temperature in Eu-doped LSCO (refs 9, 10). In the second case, two separate peaks are resolved, respectively associated with the onset of stripe order at high temperature and superconductivity near T(c).