Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD‐associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre‐incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD‐associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high‐affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD‐associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization.
(173 words)Rare coding variant in the Triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD associated TREM2 variants to various forms of Aβ and APOE in multiple assays.TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. We confirm the previous interaction between APOE3 and APOE4 and TREM2. High affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation.Pre-incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay the R47H variant decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high affinity interaction between TREM2 and Aβ oligomers that can block interaction with another ligand and ii) that AD-associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization.
One of the well reported but difficult to manage symptoms of spinal cord injury (SCI) is neurogenic lower urinary tract dysfunction (NLUTD). The type of NLUTD is variable based on location and extent of injury. SCI affects more males and NLUTD is especially debilitating for men with incomplete injury. This review summarizes the anatomical basis of NLUTD in SCI and discusses current diagnostic and management strategies that are being utilized clinically. The last two sections address new innovations and emerging discoveries with the goal of increasing scientific interest in improving treatment options for people with SCI. Areas warranting further investigation are pinpointed to address current gaps in knowledge and/or appropriate technology.
EWSR1 fusions have been identified in multiple neoplasms involving bone and soft tissue. Recently, cases of intracranial myxoid mesenchymal neoplasms harboring EWSR1-CREB family gene fusions have been reported in young patients with histologic features reminiscent of the myxoid variant of angiomatoid fibrous histiocytoma. Here, we report two cases of adult males with midline intracranial EWSR1 myxoid neoplasms. Patient 1 (age 37) presented with headaches and magnetic resonance imaging (MRI) demonstrated an enhancing right thalamic mass extending into the quadrigeminal cistern. Near-total resection was achieved, and residual disease was treated with stereotactic radiosurgery (SRS). Five-year follow-up is negative for recurrence. Patient 2 (age 28) had a past medical history significant for high-grade B-cell lymphoma of his femur and kidney for which he received systemic and intrathecal treatment. He presented to our institution with headaches, visual changes, nausea and vomiting, and MRI demonstrated a homogenously enhancing intraventricular tumor. Gross total resection was achieved, yet despite post-operative radiation therapy, he progressed 11 months later. He was then treated with radiosurgery and crizotinib, leading to stable disease 23 months after start of targeted therapy. In both cases, EWSR1 gene rearrangement was identified by fluorescence in-situ hybridization (FISH). Reverse transcription polymerase chain reaction (rt-PCR) showed a CREB1 gene fusion partner in both cases. Our cases expand the clinicopathologic features of these newly recognized tumors and include an older age at presentation and a relatively elevated proliferation index. We also present a durable response to monotherapy with a MET inhibitor in response to this gene fusion.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.