Targeting TYK2 to target tau
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Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss
Glucocorticoids (GCs) are the most prescribed anti-inflammatory and immunosuppressive drugs. However, their use is often limited by substantial side effects, such as GC-induced osteoporosis (GIO) with the underlying mechanisms still not fully understood. In this study, we identify Tau as a low-affinity binding receptor for GCs that plays a crucial role in GIO. Tau deficiency largely abolished bone loss induced by high-dose dexamethasone, a synthetic GC, in both inflammatory arthritis and GIO models. Furthermore, TRx0237, a Tau inhibitor identified from an FDA-approved drug library, effectively prevented GIO. Notably, combinatorial administration of TRx0237 and dexamethasone completely overcame the osteoporosis adverse effect of dexamethasone in treating inflammatory arthritis. These findings present Tau as a previously unrecognized GC receptor with low affinity, and provide potential strategies to mitigate a spectrum of GC-related adverse effects, particularly osteoporosis.
Alzheimer’s disease biological PET staging using plasma p217+tau
Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s disease (AD) neuropathology. However, their ability to substitute for tau PET to identify AD biological stage is unclear.
Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W
Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are the most common forms of early-onset dementia. Unlike AD, FTD begins with behavioral changes before the development of cognitive impairment. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of FTD and parkinsonism linked to chromosome 17. These individuals develop abundant filamentous tau inclusions in brain cells in the absence of β-amyloid deposits. Here, we used cryo-electron microscopy to determine the structures of tau filaments from the brains of human MAPT mutants V337M and R406W. Both amino acid substitutions gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified another assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau (297–391) with substitution V337M had the Alzheimer fold and showed an increased rate of assembly.
A multipath error cancellation method based on antenna jitter
Global Navigation Satellite System signals are often affected by multipath errors, which impact the accuracy of positioning measurements. Traditional methods frequently fail to effectively mitigate multipath errors across different environments, primarily due to their inherent sensitivity to varying conditions. Here, we propose a multipath error cancellation method that utilizes antenna jitter, which mitigates multipath errors by rapidly changing the relative phases of direct and multipath signals without requiring changes to the receiver structure. The model that combines theoretical analysis with experimental verification is conducted to identify the minimum jitter amplitude required for effective error reduction in straight-line jitter scenarios. Moreover, extensive satellite data collection and verification were performed in Changsha, China, from December 2023 to August 2024. The results indicate that the proposed method enhances robustness and applicability across various environments compared to traditional approaches. Notably, it enables a vehicle-mounted antenna, priced at just a few dollars, to achieve positioning accuracy comparable to that of high-precision antennas costing thousands of dollars, making advanced positioning technology more accessible.
Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ42/Aβ40 ratios, neurofilament light and tau in Alzheimer’s disease model mice
The Aβ42/Aβ40 ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed in the early stages of Alzheimer’s disease (AD)1, but their neurobiological correlates are not entirely understood. Here, we used 5xFAD transgenic mice to investigate the associations between these CSF biomarkers and measures of cerebral Aβ, including Aβ42/Aβ40 ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high Aβ42/Aβ40 ratio in soluble protofibrils was the strongest independent predictor of low CSF Aβ42/Aβ40 ratios and high CSF NfL and t-tau concentrations when compared to Aβ42/Aβ40 ratios in plaques and insoluble fibrillar deposits. Furthermore, the Aβ42/Aβ40 ratio in soluble protofibrils fully mediated the associations between the corresponding ratio in plaques and all the investigated CSF biomarkers. In AppNL-G-F/NL-G-F knock-in mice, protofibrils fully mediated the association between plaques and the CSF Aβ42/Aβ40 ratio. Together, the results suggest that the Aβ42/Aβ40 ratio in CSF might better reflect brain levels of soluble Aβ protofibrils than insoluble Aβ fibrils in plaques in AD. Furthermore, elevated concentrations of NfL and t-tau in CSF might be triggered by increased brain levels of soluble Aβ protofibrils.
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