A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

Tumor necrosis factor in serum and cerebrospinal fluid of patients with multiple sclerosis

We measured levels of alpha-tumor necrosis factor (\u3b1-TNF) in cerebrospinal fluid and serum samples from 50 drug-free patients with multiple sclerosis, 25 patients with other neurological diseases, 27 patients with non-neurological diseases, and 10 normal subjects. The most elevated levels of \u3b1-TNF were found in patients with inflammatory or autoimmune diseases. Comparable serum levels of \u3b1-TNF were detected in normal control subjects, patients with multiple sclerosis, and patients with degenerative neurological diseases. In patients with multiple sclerosis, \u3b1-TNF levels were also unrelated to time elapsed between the occurrence of clinical exacerbation and the time of sample collection. Only 3 patients with chronic progressive multiple sclerosis had detectable \u3b1-TNF in the cerebrospinal fluid. Our data do not support a role for elevated levels of circulating \u3b1-TNF in the maintenance of the disease. However, we cannot rule out the possibility that a transient elevation of \u3b1-TNF triggers the cellular events leading to demyelination in multiple sclerosis

Isoelectric focusing herpes simplex virus-gB overlay study in brainstem encephalitis

We report a case of herpetic brainstem encephalitis (HBE) retrospectively diagnosed in an adult patient. Conventional immunovirological studies failed to disclose the etiology of this patient's affection. An isoelectric focusing-antigen overlay (IEF-O) technique showed that the target of one of the four cerebrospinal fluid oligoclonal bands was herpes simplex virus (HSV)-1 glycoprotein B, indicating a specific anti-HSV immunoresponse restricted to the CNS. IEF-O may represent a useful support for in vivo diagnosis of HBE

Acute Guillain-Barr\ue9 syndrome associated with asymptomatic HIV infection

A 25-year-old male drug addict presented with a rapidly progressive ascending tetraplegia, requiring assisted ventilation. One month earlier he had fever (40 degrees C) and asthenia. Cerebrospinal fluid (CSF) examination showed elevated albumin level and albuminocytologic dissociation. HIV testing was positive in both serum and CSF. Plasma exchange therapy only partially improved the symptomatology. After five months the patient remained with a moderate tetraparesis. Differences between this and other cases of Guillain-Barr\ue9 syndrome in HIV-seropositive patients reported in the literature are discussed