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Hyperphosphorylation and aggregation of the protein tau play key roles in the development of Alzheimer's disease (AD). While the molecular structure of the filamentous tau aggregates has been determined to atomic resolution, there is far less information available about the smaller, soluble aggregates, which are believed to be more toxic. Traditional techniques are limited to bulk measures and struggle to identify individual aggregates in complex biological samples. To address this, we developed a novel single‐molecule pull‐down‐based assay (MAPTau) to detect and characterize individual tau aggregates in AD and control post‐mortem brain and biofluids. Using MAPTau, we report the quantity, as well as the size and circularity of tau aggregates measured using super‐resolution microscopy, revealing AD‐specific differences in tau aggregate morphology. By adapting MAPTau to detect multiple phosphorylation markers in individual aggregates using two‐color coincidence detection, we derived compositional profiles of the individual aggregates. We find an AD‐specific phosphorylation profile of tau aggregates with more than 80 % containing multiple phosphorylations, compared to 5 % in age‐matched non‐AD controls. Our results show that MAPTau is able to identify disease‐specific subpopulations of tau aggregates phosphorylated at different sites, that are invisible to other methods and enable the study of disease mechanisms and diagnosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The "prion‐like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid‐β (Aβ) have never been experimentally studied in primates phylogenetically close to humans. METHODS: We injected 17 macaques in the entorhinal cortex with nanograms of seeding‐competent tau aggregates purified from AD brains or control extracts from aged‐matched healthy brains, with or without intracerebroventricular co‐injections of oligomeric‐Aβ. RESULTS: Pathological tau injection increased cerebrospinal fluid (CSF) p‐tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD‐related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total‐tau concentration, and pre‐ and postsynaptic degeneration only in Aβ co‐injected macaques. DISCUSSION: Oligomeric‐Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. Highlights: This study supports the "prion‐like" properties of misfolded tau extracted from AD brains.This study empirically validates the Braak staging in an anthropomorphic brain.This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology.This work establishes a novel animal model of early sporadic AD that is closer to the human pathology. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Signatures of a type‐I interferon (IFN‐I) response are observed in the post mortem brain in Alzheimer's disease (AD) and other tauopathies. However, the effect of the IFN‐I response on pathological tau accumulation remains unclear. METHODS: We examined the effects of IFN‐I signaling in primary neural culture models of seeded tau aggregation and P301S‐tau transgenic mouse models in the context of genetic deletion of the IFN‐I receptor (IFNAR). RESULTS: Polyinosinic:polycytidylic acid (PolyI:C), a synthetic analog of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau in an IFN‐I‐dependent manner. IFN‐I‐induced vulnerability could be pharmacologically prevented and was intrinsic to neurons. Aged P301S‐tau mice lacking Ifnar1 had significantly reduced tau pathology compared to mice with intact IFN signaling. DISCUSSION: We identify a critical role for IFN‐I in potentiating tau aggregation. IFN‐I is therefore identified as a potential therapeutic target in AD and other tauopathies. Highlights: Type‐I IFN (IFN‐I) promotes seeded tau aggregation in neural cultures.IFNAR inhibition prevents IFN‐I driven sensitivity to tau aggregation.IFN‐I driven vulnerability is intrinsic to neurons.Tau pathology is significantly reduced in aged P301S‐tau mice lacking IFNAR. [ABSTRACT FROM AUTHOR]

The article focuses on the implications of the Major Questions Doctrine, as demonstrated in the Supreme Court case West Virginia v. EPA, for decision-making by healthcare agencies, particularly the CDC (Centers for Disease Control and Prevention). It examines the potential impact of judicial review standards on agency authority and regulatory actions in the context of public health crises.

Progressive supranuclear palsy (PSP) is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that PSP tauopathy may spread in the brain from cell to cell in a "prion-like" manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of PSP patients. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of PSP-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pFTAA positive), and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of PSP-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that PSP-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as six months after injection, remaining present until sacrifice at 18 months. Object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in PSP-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in PSP-tau injected macaques. Characteristic pathological hallmarks of PSP, including globose and neurofibrillary tangles, tufted astrocytes, and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in PSP (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that PSP patient-derived tau aggregates can induce motor and behavioral impairments in non-human primates related to the prion-like seeding and spreading of typical pathological PSP lesions. This pilot study pave the way for supporting PSP-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease. [ABSTRACT FROM AUTHOR]