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Item A framework for translating tauopathy therapeutics: Drug discovery to clinical trials(Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of MedicineThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.Item Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein(Society for Neuroscience, 2002-11) Allen, Bridget; Ingram, Esther; Takao, Masaki; Smith, Michael J.; Jakes, Ross; Virdee, Kanwar; Yoshida, Hirotaka; Holzer, Max; Craxton, Molly; Emson, Piers C.; Atzori, Cristiana; Migheli, Antonio; Crowther, R. Anthony; Ghetti, Bernardino; Spillantini, Maria Grazia; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineThe identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.Item Classification of Diseases with Accumulation of Tau(Wiley, 2022) Kovacs, Gabor G.; Ghetti, Bernardino; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineItem The Influence of Genetic Diversity on Tauopathy(2024-02) Acri, Dominic James; Oblak, Adrian L.; Kim, Jungsu; Landreth, Gary E.; Lasagna-Reeves, Cristian A.; Liu, YunlongThe presence of misfolded tau proteins is a hallmark of a group of neurodegenerative diseases termed tauopathies. This heterogeneous group of disorders includes Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, and dozens of related dementias. One common approach to research these diseases is to use clonally inbred animal strains to investigate druggable pathways that can be translated to human patients. Although clonally inbred lines offer a standard to limit inter-laboratory variability, selecting a single genetic background does not allow researchers to consider the natural population-level genetic diversity seen in humans. Recent studies have demonstrated that introducing genetic diversity into animal models of complex diseases improves translatability to patient populations. Within the context of neurodegeneration, several studies have found that brain pathology in mouse models of amyloid-β accumulation is modified by genetic variance within a subset of wild-derived mouse strains. Several findings have demonstrated that non-C57BL/6J mouse strains alter tau pathology, however, the effect of these wild-derived strains on tau is unknown. To understand how genetically diverse animal models respond to the presence of pathological tau, we generated cohorts of wild-derived mice and fruit flies that express humanized mutant tau. We found that the formation of proteopathic prion-like tau seeds was dependent on the genetic backgrounds of these wild-derived animal models. Interestingly, we showed that multi-omic analysis of PWK/PhJ reveals immune dysregulation not seen in classically inbred models of tau pathology. Furthermore, genetic mapping in a novel panel of wild-derived fruit flies revealed novel genetic modifiers of tau seeds. We demonstrate how tauopathy is influenced by genetic diversity and how these models may be used as a resource to study tau-driven neurodegenerative diseases. Taken together, the data suggest that introducing genetic diversity into animal models of mutant tau expression may increase translation to patients suffering from tauopathy.Item Transcriptional risk scores in Alzheimer's disease: From pathology to cognition(Wiley, 2024) Pyun, Jung-Min; Park, Young Ho; Wang, Jiebiao; Bennett, David A.; Bice, Paula J.; Kim, Jun Pyo; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; Radiology and Imaging Sciences, School of MedicineIntroduction: Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS. Methods: We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS). Results: Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850. Discussion: Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker. Highlights: Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.Item TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo(MDPI, 2023-06-10) Lee-Gosselin, Audrey; Jury-Garfe, Nur; You, Yanwen; Dabin, Luke; Soni, Disha; Dutta, Sayan; Rochet, Jean-Christophe; Kim, Jungsu; Oblak, Adrian L.; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of MedicineThe role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.Item Triggering receptor expressed on myeloid cells 2 deficiency exacerbates injury-induced inflammation in a mouse model of tauopathy(Frontiers Media, 2022-11-01) Katsumoto, Atsuko; Kokiko-Cochran, Olga N.; Bemiller, Shane M.; Xu, Guixiang; Ransohoff, Richard M.; Lamb, Bruce T.; Medical and Molecular Genetics, School of MedicineTraumatic brain injury (TBI) promotes several Alzheimer's disease-like pathological features, including microtubule-associated protein tau (MAPT) accumulation within neurons. Macrophage activation in the injured hTau mouse model of tauopathy raises the question whether there is a relationship between MAPT pathology and alterations in macrophage activation following TBI. Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical regulator of microglia and macrophage phenotype, but its mechanisms on TBI remain unclear. To address the association with TREM2 in TBI and MAPT pathology, we studied TREM2 deficiency in hTau mice (hTau;Trem2-/- ) 3 (acute phase) and 120 (chronic phase) days after experimental TBI. At three days following injury, hTau;Trem2-/- mice exhibited reduced macrophage activation both in the cortex and hippocampus. However, to our surprise, hTau;Trem2-/- mice exposed to TBI augments macrophage accumulation in the corpus callosum and white matter near the site of tissue damage in a chronic phase, which results in exacerbated axonal injury, tau aggregation, and impaired neurogenesis. We further demonstrate that TREM2 deficiency in hTau injured mice promotes neuronal dystrophy in the white matter due to impaired phagocytosis of apoptotic cells. Remarkably, hTau;Trem2-/- exposed to TBI failed to restore blood-brain barrier integrity. These findings imply that TREM2 deficiency accelerates inflammation and neurodegeneration, accompanied by attenuated microglial phagocytosis and continuous blood-brain barrier (BBB) leakage, thus exacerbating tauopathy in hTau TBI mice.