Steven L. Carroll

Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Individuals with Down syndrome (DS) exhibit Alzheimers disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as non‐AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid β (Aβ) peptides and phosphorylated‐tau in neuronal exosomes may document preclinical AD.

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms: Malignant Peripheral Nerve Sheath Tumors as a Paradigm for Cross-Species Comparative Oncogenomics.

Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cell-derived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1-associated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16(INK4A)-cyclin D1-CDK4-Rb and p19(ARF)-Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis.

STAT1 and NF-κB Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells

Interferon-stimulated genes (ISG) encode diverse proteins that mediate intrinsic antiviral resistance in infected cells. Here it was hypothesized that malignant peripheral nerve sheath tumor (MPNST) cells resist the productive infection of oncolytic herpes simplex virus (oHSV) through activation of the JAK/STAT1 pathway and resultant upregulation of ISGs. Multiple human and mouse MPNST cells were used to explore the relationship between STAT1 activation and the productive infection of Δγ134.5 oHSVs. STAT1 activation in response to oHSV infection was found to associate with diminished Δγ134.5 oHSVs replication and spread. Multiday pretreatment, but not cotreatment, with a JAK inhibitor significantly improved viral titer and spread. ISG expression was found to be elevated prior to infection and downregulated when treated with the inhibitor, suggesting that the JAK/STAT1 pathway is active prior to infection. Conversely, upregulation of ISG expression in normally permissive cells significantly decreased oHSV productivity. Finally, a possible link between NF-κB pathway activation and ISG expression was established through the expression of inhibitor of kB (IκB) which decreased basal STAT1 transcription and ISG expression. These results demonstrate that basal ISG expression prior to infection contributes to the resistance of Δγ134.5 oHSVs in MPNST cells. Implications: Although cancer-associated ISG expression has been previously reported to impart resistance to chemotherapy and radiotherapy, these data show that basal ISG expression also contributes to oncolytic HSV resistance. Mol Cancer Res; 14(5); 482–92. ©2016 AACR.

Current status and recommendations for biomarkers and biobanking in neurofibromatosis

Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working groups goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. Results: We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN.

Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer’s Disease

Alzheimers disease (AD) is the most common form of dementia that is often accompanied by mood and emotional disturbances and seizures. There is growing body of evidence that neurons expressing γ-aminobutyric acid (GABA) play an important role in regulation of cognition, mood, and emotion as well as seizure susceptibility, but participation of GABAergic neuronal pathology in Alzheimers disease (AD) is not understood well at present. Here, we report that transgenic mice expressing human amyloid precursor protein Swedish-Dutch-Iowa mutant (APPSweDI) exhibit early loss of neurons expressing GAD67, a GABA-synthesizing enzyme, in advance of the loss of pyramidal neurons in hippocampal CA1 region. The loss of GAD67+ neurons in APPSweDI mice accompanied with decreased spatial cognition as well as increased anxiety-like behaviors and kainic acid-induced seizure susceptibility at early phase. In the hippocampal CA1 region, GAD67+ neurons expressed high basal levels of neuronal nitric oxide synthase (nNOS) and nitrosative stress (nitrotyrosine). Similarly, GAD67+ neurons in primary cortical and hippocampal neuron cultures also expressed high basal levels of nNOS and degenerated in response to lower Aβ concentrations due to their high basal levels of nitrosative stress. Given the role of GABAergic neurons in cognitive and neuropsychiatric functions, this study reports the role of nNOS-mediated nitrosative stress in dysfunction of GABAergic neurons and its potential participation in early development of cognitive and neuropsychiatric symptoms in AD.

The Molecular and Morphologic Structures That Make Saltatory Conduction Possible in Peripheral Nerve

Saltatory conduction is the process by which action potentials are rapidly and efficiently propagated along myelinated axons. In the peripheral nervous system, saltatory conduction is made possible by a series of morphologically and molecularly distinct subdomains in both axons and their associated myelinating Schwann cells. This review briefly summarizes current knowledge on the molecular structure and physiology of the node of Ranvier and adjacent regions of the axoglial unit in peripheral nerve.