Minocycline prevents cholinergic loss in a mouse model of Down's syndrome.
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.
Hunter
Christopher L
CL
Medical University of South Carolina, Department of Neuroscience, and the Center on Aging, Charleston, SC 29425, USA.
Bachman
David
D
Granholm
Ann-Charlotte
AC
D000109:Acetylcholine / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D064032:Calbindin 2; D064026:Calbindins; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D004924:Escape Reaction / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008911:Minocycline / Q000627:therapeutic use*; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D064032:Calbindin 2; D064026:Calbindins; D064030:S100 Calcium Binding Protein G; D002795:Choline O-Acetyltransferase; D017493:Leukocyte Common Antigens; D008911:Minocycline; D000109:Acetylcholine