Astrocyte signaling and neurodegeneration: new insights into CNS disorders

Abstract

Growing evidence indicates that astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal activity and survival, but rather they are involved in a striking number of active functions that are critical to the performance of the central nervous system (CNS). As a consequence, it is becoming more and more evident that the peculiar properties of these cells can actively contribute to the extraordinary functional complexity of the brain and spinal cord. This new perception of the functioning of the CNS opens up a wide range of new possibilities to interpret various physiological and pathological events, and moves the focus beyond the neuronal compartment toward astrocyte-neuron interactions. With this in mind, here we provide a synopsis of the activities astrocytes perform in normal conditions, and we try to discuss what goes wrong with these cells in specific pathological conditions, such as Alzheimer Disease, prion diseases and amyotrophic lateral sclerosis.

Keywords: Alzheimer disease; Amyotrophic Lateral Sclerosis; Ca2+; astrocytes; glutamate; prion diseases.

Figure 1. Impaired TNFα-dependent glutamate release from hippocampal astrocytes of scrapie-infected mice. Histograms indicate the glutamate release induced by TNFα (30ng/ml) in acute hippocampal slices from C57Bl/6J mice intracerebrally (30 μl, (A) or intraperitoneally (100 μl, (B) inoculated with 1% homogenate from saline-treated (CTRL) or RML-infected, terminally ill CD1 mouse brains. Brains were taken at 14, 90 and 135 d post intracerebral inoculation (d.p.i.) and at 14 and 180 d post intraperitoneal inoculation (Days to terminal disease: i.c.: 164 ± 3; i.p.: 209 ± 5). Acute hippocampal slices were prepared and the amount of glutamate released upon stimulation with TNFα was measured using a previously described enzymatic assay. Data are expressed as mean ± s.e.m. (n = 3–6 animals for each experimental group). *p < 0.05 vs. CTRL, two-way ANOVA followed by Scheffe’s F-test.

Figure 2. Progressive astrocytosis and spongiosis in the hippocampus of scrapie-infected mice. Coronal sections from saline-treated (CTRL) and RML-infected animals (i.c.) at 90 and 135 d.p.i were stained with hematoxylin alone or hematoxylin with the astrocytic marker Glial Fibrillary Acidic Protein (GFAP). Stainings highlight spongiosis and pronounced astrocytosis in the hippocampus of RML-infected mice at 135 d.p.i. Images are representative of 3 animals. Scale bar, 50μm.

Figure 3. PrP^Sc accumulation and prion titers in the hippocampus of RML-infected mice. (A) Hippocampal homogenates from saline-treated (CTRL) or RML-infected mice (i.c.) at 14, 90 and 135 d.p.i. were treated in the presence (+) or in the absence (-) of proteinase K to distinguish native PrP^C from the proteinase K-resistant PrP^Sc and analyzed by western blotting (n = 3). (B) Prion titers in the hippocampus of infected animals at 14, 90 and 135 d.p.i. were determined by inoculating homogenates i.c. into CD-1 indicator mice. Data highlight a progressive increase in the amount of PrP^Sc and infectivity in the hippocampi of RML-infected mice at 135 d.p.i. n/nt = Number of mice with scrapie/ total number of mice inoculated.