BackgroundRecent in vitro and in vivo data show that Tau‐RNA complexes contribute to neuronal dysfunction. However, whether these complexes appear in human tauopathy brains, and whether they are inherently toxic remains unknown. Clarifying the dynamics of tau‐RNA interactions and its relevance in disease would reveal critical and urgently needed information to determine novel therapeutic targets.MethodHuman Alzheimer’s and age‐matched non‐demented control brains were subjected to enhanced cross‐linking immunoprecipitation (eCLIP) sequencing. Amount of RNA was quantified and sequenced in each group. Cell culture experiments were used to validate eCLIP data.ResultTau associated robustly with RNA, many of which have not been previously reported. Early and late‐stage AD tau‐RNA complexes shifted from coding to non‐coding sequences. The consensus sequences that associated with tau contain numerous splice sites and start codons. RNA‐stabilizing species associated with tau in AD brains. Tau overexpression impaired RNA processing, transport, and translation in vitro.ConclusionTau‐RNA interactions, that have not been previously reported, were identified for the first time in human AD brains, and they reveal novel sequences that could be associated with disease.

BackgroundThe risk of Alzheimer’s Disease (AD) is associated with muscle weakness, but the molecular basis of this association is unknown. Beyond motor function, skeletal muscle is a highly metabolic endocrine organ, and it crosstalks with other systems. Therefore, disruptions in skeletal muscle health may influence whole‐body homeostasis with AD progression. Accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD. Neurodegeneration could negatively impact muscle function; likewise, dysfunctional skeletal muscle can also deleteriously impact the environment of whole‐body processes, including tau pathogenesis. Therefore, measuring temporal changes in muscle function relative to insoluble tau accumulation would offer insight into whether skeletal muscle contributes to the progression of tau pathology.MethodsMale and female inducible muscle specific Bmal1 knockout (iMSBmal1KO) mice were used to model muscle weakness. Intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (n= 15) and yellow fluorescent protein (YFP) (n=18) were done at postnatal day 0. Grip strength, rotarod, and body composition were measured at 16 weeks. At 18 weeks, intraperitoneal injections were performed with either tamoxifen (n=8 tau, 11 YFP) or corn oil (n=7 tau, 7 YFP) to delete the core clock gene Bmal1 exclusively in skeletal muscle. Brains were harvested at 24 weeks. Soluble and insoluble tau were biochemically measured after a sarkosyl extraction protocol. Immunohistochemistry was performed. An additional cohort of wildtype C57BL/6 mice were intracerebroventricularly injected with AAV‐P301L human tau (n= 11) and the empty AAV construct (n= 10). Grip strength was measured at 10 and 12 weeks.ResultsGrip strength was reduced at 16 weeks in the mutant tau treated iMSBmal1KO mice, two weeks before induced muscle weakness, and 10 weeks before NFTs are reported in this tauopathy model. Insoluble tau was detected biochemically at 24 weeks. Grip strength was reduced in tau treated wildtype mice at 10 and 12 weeks.ConclusionsChanges in grip strength preceded NFT formation in this tauopathy model in both iMSBmal1 transgenic and wildtype mice. This suggests that a) muscle weakness may serve as a biomarker and b) that disrupted skeletal muscle health may be capable of contributing to tauopathy progression.

BackgroundA major challenge in the field of tauopathies, such as progressive supranuclear palsy (PSP) is identification of effective therapeutic targets. PKR‐like endoplasmic reticulum (ER) kinase haplotype A (PERK‐A) adapts cells undergoing ER stress. PERK haplotype B (PERK‐B) does not resolve ER stress effectively and increases the risk for PSP. The mechanism by which PERK‐A and ‐B confer distinct outcomes remains unknown. The overall hypothesis is that PERK‐B promotes maladaptive response that increases tauopathy outcomes.MethodsWe developed new inducible cell lines, unfolded protein response sensors, and PERK plasmids (‐A, ‐B, and an inactive variant, ‐K). We performed molecular biology approaches in vitro including co‐expression, co‐immunoprecipitation assays, and RNAseq.ResultsWe found that unlike PERK‐A, PERK‐B was not an effective modulator of pathological tau species. The transcriptome and translatome of PERK‐A and ‐B are distinct. Surprisingly, the PERK‐A translatome has pro‐survival factors.ConclusionPERK‐A confers benefits in tauopathy. The PERK‐A translatome is replete with novel therapeutic targets. PERK‐B data offer novel insights into the pathogenesis and progression of PSP, which may be linked to other tauopathies.