minocycline and Down-Syndrome

Down's syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.

Topics: Animals; Astrocytes; Case-Control Studies; Cell Differentiation; Cell Survival; Cell Transplantation; Culture Media, Conditioned; Down Syndrome; Gene Expression Profiling; Glial Fibrillary Acidic Protein; Homeodomain Proteins; Humans; Induced Pluripotent Stem Cells; Mice, Inbred C57BL; Mice, Mutant Strains; Minocycline; Neural Stem Cells; Neurons; Nitric Oxide Synthase Type II; S100 Calcium Binding Protein beta Subunit; Thrombospondin 1; Thrombospondins

Individuals with Down's syndrome develop Alzheimer's-like pathologies comparatively early in life, including progressive degeneration of basal forebrain cholinergic neurons (BFCNs). Cholinergic hypofunction contributes to dementia-related cognitive decline and remains a target of therapeutic intervention for Alzheimer's disease. In light of this, partial trisomy 16 (Ts65Dn) mice have been developed to provide an animal model of Down's syndrome that exhibits progressive loss of BFCNs and cognitive ability. Another feature common to both Down's syndrome and Alzheimer's disease is neuroinflammation, which may exacerbate neurodegeneration, including cholinergic loss. Minocycline is a semisynthetic tetracycline with antiinflammatory properties that has demonstrated neuroprotective properties in certain disease models. Consistent with a role for inflammatory processes in BFCN degeneration, we have shown previously that minocycline protects BFCNs and improves memory in mice with acute, immunotoxic BFCN lesions. We now report that minocycline treatment inhibits microglial activation, prevents progressive BFCN decline, and markedly improves performance of Ts65Dn mice on a working and reference memory task. Minocycline is an established antiinflammatory and neuroprotective drug and may provide a novel approach to treat specific AD-like pathologies.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Behavior, Animal; Brain; Calbindin 2; Calbindins; Cell Count; Choline O-Acetyltransferase; Cholinergic Fibers; Disease Models, Animal; Down Syndrome; Escape Reaction; Immunohistochemistry; Leukocyte Common Antigens; Male; Maze Learning; Memory; Mice; Mice, Mutant Strains; Microglia; Minocycline; Nerve Degeneration; S100 Calcium Binding Protein G