A Model of Traumatic Brain Injury Oligomerizes Tau in Cortical Organoids and Induces Clinically Relevant Pathologies that Synergize with Mutation.

Traumatic brain injury (TBI) is the most important environmental risk factor for neurodegenerative disease. Tauopathy plays an important role in post-traumatic neurodegeneration. Human-induced pluripotent stem cell (hiPSC)-derived cortical organoids have exciting potential to reveal the influence of genotype on post-traumatic neurodegeneration because they permit manipulation of the genome in a human system.

Single-cell transcriptome and surfaceome profiling of the adult human retinal pigment epithelium.

The retinal pigment epithelium (RPE) is a pigmented monolayer of cells beneath the neural retina that supports photoreceptor cell function essential for vision. Our study explores the diversity of adult human RPE subpopulations and associated implications for retinal biology. Employing cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we identified distinct RPE cell subpopulations characterized by unique single-cell transcriptomic and surface protein signatures.

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau.

Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that MAPT mRNA and tau protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs).

Cryoelectrospun elastin-alginate scaffolds as potential cell delivery vehicles for mesenchymal stromal cell therapy.

Salivary gland fibrosis results in salivary hypofunction whose current treatments are palliative. Mesenchymal stem/stromal cells (MSCs) are anti-fibrotic and anti-inflammatory and provide a promising alternative to treat fibrosis, but face translational challenges due to poor tissue targeting and retention. Scaffolds could facilitate targeted MSC delivery and improve MSC retention.

Insights into pathophysiology, biomarkers, and therapeutics in tauopathies: Proceedings of the Tau2024 Global Conference.

Recent years have seen major advances in tau-associated brain disorders through interdisciplinary research spanning molecular biology, neuroimaging, clinical trials, and therapeutic development. The Tau2024 Global Conference, hosted by the Alzheimer's Association, CurePSP, and Rainwater Charitable Foundation, showcased these efforts by bringing together researchers and experts worldwide to discuss the latest advancements in tau research. The conference aimed to attract talent and funding to study tauopathies, particularly among early-career researchers, and to foster interdisciplinary alignment and collaboration around challenges in tau research.

Herpes simplex virus-1 infection alters microtubule-associated protein Tau splicing and promotes Tau pathology in neural models of Alzheimer's disease.

Herpes simplex virus 1 (HSV-1) infection alters critical markers of Alzheimer's disease (AD) in neurons. One key marker of AD is the hyperphosphorylation of Tau, accompanied by altered levels of Tau isoforms. However, an imbalance in these Tau splice variants, specifically resulting from altered 3R to 4R MAPT splicing of exon 10, has yet to be directly associated with HSV-1 infection.

Pathways underlying selective neuronal vulnerability in Alzheimer's disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra.

Introduction: Alzheimer's disease (AD) selectively affects certain brain regions, yet the mechanisms of selective vulnerability remain poorly understood. The neuromodulatory subcortical system, which includes nuclei exhibiting a range of vulnerability and resilience to AD-type degeneration, presents a framework for uncovering these mechanisms.

Methods: We leveraged transcriptomics and immunohistochemistry in paired samples from human post mortem tissue representing a vulnerable and resilient region-the locus coeruleus (LC) and substantia nigra (SN).

Interactions between menopause and high-fat diet on cognition and pathology in a mouse model of Alzheimer's disease.

Introduction: Post-menopausal women constitute about two-thirds of those with Alzheimer's disease (AD). Menopause increases dementia risk by heightening the likelihood of metabolic disease, a well-known risk factor for dementia. We aimed to determine the effects of menopause and high-fat diet (HF) on cognitive and pathological outcomes in an AD mouse model.

A framework for neural organoids, assembloids and transplantation studies.

As the field of neural organoids and assembloids expands, there is an emergent need for guidance and advice on designing, conducting and reporting experiments to increase the reproducibility and utility of these models. In this Perspective, we present a framework for the experimental process that encompasses ensuring the quality and integrity of human pluripotent stem cells, characterizing and manipulating neural cells in vitro, transplantation techniques and considerations for modelling human development, evolution and disease. As with all scientific endeavours, we advocate for rigorous experimental designs tailored to explicit scientific questions as well as transparent methodologies and data sharing to provide useful knowledge for current research practices and for developing regulatory standards.

iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death.

Background: Tau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology.

ENGINEERED NANOBODIES WITH PROGRAMMABLE TARGET ANTIGEN PROTEOLYSIS (PTAP) FUSIONS REGULATE INTRACELLULAR ALPHA-SYNUCLEIN IN VITRO AND IN VIVO.

Alpha-synuclein (αSyn) aggregation and the formation of Lewy pathology (LP) is a foundational pathophysiological phenomenon in synucleinopathies. Delivering therapeutic single-chain and single-domain antibodies that bind pathogenic targets can disrupt intracellular aggregation. The fusion of antibody fragments to a negatively-charged proteasomal targeting motif (PEST) creates bifunctional constructs that enhance both solubility and turnover.

Recommendations for the collection and annotation of biosamples for analysis of biomarkers in neurofibromatosis and schwannomatosis clinical trials.

Introduction: Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease.

Interfacing neural cells with typical microelectronics materials for future manufacturing.

The biocompatibility of materials used in electronic devices is critical for the development of implantable devices like pacemakers and neuroprosthetics, as well as in future biomanufacturing. Biocompatibility refers to the ability of these materials to interact with living cells and tissues without causing an adverse response. Therefore, it is essential to evaluate the biocompatibility of metals and semiconductor materials used in electronic devices to ensure their safe use in medical applications.

Adult Mouse Leptomeninges Exhibit Regional and Age-related Cellular Heterogeneity Implicating Mental Disorders.

The leptomeninges envelop the central nervous system (CNS) and contribute to cerebrospinal fluid (CSF) production and homeostasis. We analyzed the meninges overlying the anterior or posterior forebrain in the adult mouse by single nuclear RNA-sequencing (snucRNA-seq). This revealed regional differences in fibroblast and endothelial cell composition and gene expression.

Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells.

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats.

Direct differentiation of human pluripotent stem cells into vascular network along with supporting mural cells.

During embryonic development, endothelial cells (ECs) undergo vasculogenesis to form a primitive plexus and assemble into networks comprised of mural cell-stabilized vessels with molecularly distinct artery and vein signatures. This organized vasculature is established prior to the initiation of blood flow and depends on a sequence of complex signaling events elucidated primarily in animal models, but less studied and understood in humans. Here, we have developed a simple vascular differentiation protocol for human pluripotent stem cells that generates ECs, pericytes, and smooth muscle cells simultaneously.

Advancing cell therapy for neurodegenerative diseases.

Cell-based therapies are being developed for various neurodegenerative diseases that affect the central nervous system (CNS). Concomitantly, the roles of individual cell types in neurodegenerative pathology are being uncovered by genetic and single-cell studies. With a greater understanding of cellular contributions to health and disease and with the arrival of promising approaches to modulate them, effective therapeutic cell products are now emerging.

Stem cell sources and characterization in the development of cell-based products for treating retinal disease: An NEI Town Hall report.

National Eye Institute recently issued a new Strategic Plan outlining priority research areas for the next 5 years. Starting cell source for deriving stem cell lines is as an area with gaps and opportunities for making progress in regenerative medicine, a key area of emphasis within the NEI Strategic Plan. There is a critical need to understand how starting cell source affects the cell therapy product and what specific manufacturing capabilities and quality control standards are required for autologous vs allogeneic stem cell sources.

Rewired mA epitranscriptomic networks link mutant p53 to neoplastic transformation.

N6-methyladenosine (mA), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of mA epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas.

Conserved gene signatures shared among mutations reveal defects in calcium signaling.

More than 50 mutations in the gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau.

Temporary induction of hypoxic adaptations by preconditioning fails to enhance Schwann cell transplant survival after spinal cord injury.

Hypoxic preconditioning is protective in multiple models of injury and disease, but whether it is beneficial for cells transplanted into sites of spinal cord injury (SCI) is largely unexplored. In this study, we analyzed whether hypoxia-related preconditioning protected Schwann cells (SCs) transplanted into the contused thoracic rat spinal cord. Hypoxic preconditioning was induced in SCs prior to transplantation by exposure to either low oxygen (1% O ) or pharmacological agents (deferoxamine or adaptaquin).

Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration.

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration.

Single cell profiling of CD45 spinal cord cells reveals microglial and B cell heterogeneity and crosstalk following spinal cord injury.

Background: Immune cells play crucial roles after spinal cord injury (SCI). However, incomplete knowledge of immune contributions to injury and repair hinders development of SCI therapies. We leveraged single-cell observations to describe key populations of immune cells present in the spinal cord and changes in their transcriptional profiles from uninjured to subacute and chronic stages of SCI.

Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.

The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose metabolism-to DR. Using human tissue and genetically manipulated mice (including RPE-specific conditional knockout (cKO) and knock-in (KI) mice), we investigate whether Akts in the RPE influences DR in models of diabetic eye disease.