Mutant tau filaments from some inherited frontotemporal dementias show the Alzheimer fold
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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.
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.
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.
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.
AAV8-P301L tau expression confers age-related disruptions in sleep quantity and timing
Sleep timing and quantity disturbances persist in tauopathy patients. This has been studied in transgenic models of primary tau neuropathology using traditional electroencephalograms (EEGs) and more recently, the PiezoSleep Mouse Behavioral Tracking System. Here, we generated a primary tauopathy model using an intracerebroventricular injection of human mutant hSyn-P301L-tau, using adeno-associated virus of serotype 8 (AAV8). We discovered distinctions in sleep architecture with altered quantity and timing in AAV8-P301L tau expressing mice of both sexes using the noninvasive PiezoSleep System. The AAV8-P301L tau mice exhibit striking age-related increases in sleep duration specifically at the active phase onset, suggesting a critical and sensitive time-of-day for tauopathy related sleep disturbances to occur. Since our findings show sleep behavior changes at specific transitional periods of the day, tau neuropathology may impact normal diurnal variation in biological processes, which should be explored using the AAV8-P301L tauopathy model.
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