Minocycline prevents cholinergic loss in a mouse model of Down's syndrome

Ann Neurol. 2004 Nov;56(5):675-88. doi: 10.1002/ana.20250.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / deficiency*
  • Acetylcholine / metabolism
  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Behavior, Animal / drug effects
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism
  • Calbindin 2
  • Calbindins
  • Cell Count / methods
  • Choline O-Acetyltransferase / metabolism
  • Cholinergic Fibers / drug effects
  • Cholinergic Fibers / metabolism
  • Disease Models, Animal
  • Down Syndrome / complications
  • Down Syndrome / drug therapy*
  • Down Syndrome / genetics
  • Escape Reaction / drug effects
  • Immunohistochemistry / methods
  • Leukocyte Common Antigens / metabolism
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects
  • Mice
  • Mice, Mutant Strains
  • Microglia / drug effects
  • Microglia / metabolism
  • Minocycline / therapeutic use*
  • Nerve Degeneration / etiology
  • Nerve Degeneration / prevention & control*
  • S100 Calcium Binding Protein G / metabolism


  • Anti-Inflammatory Agents
  • Calbindin 2
  • Calbindins
  • S100 Calcium Binding Protein G
  • Choline O-Acetyltransferase
  • Leukocyte Common Antigens
  • Minocycline
  • Acetylcholine