Minocycline Protects Basal Forebrain Cholinergic Neurons From Mu p75-saporin Immunotoxic Lesioning

Eur J Neurosci. 2004 Jun;19(12):3305-16. doi: 10.1111/j.0953-816X.2004.03439.x.

Abstract

Two prominent characteristics of Alzheimer's disease are basal forebrain cholinergic degeneration and neuroinflammation characterized by glial activation and the release of pro-inflammatory cytokines. Mu p75- saporin (SAP) is a novel immunotoxin that mimics the selective loss of basal forebrain cholinergic neurons and induces cognitive impairment in mice. We report that cholinergic cell loss in the medial septal nucleus and ventral diagonal band after i.c.v. injection of mu p75-SAP is accompanied by simultaneous activation of microglia and astrocytes in the basal forebrain region as well as significant memory loss. Consistent with a role of glial cells in the pathology of Alzheimer's disease, minocycline, a second-generation tetracycline with known anti-inflammatory and neuroprotective properties, attenuated mu p75-SAP-induced cholinergic cell loss, glial activation and transcription of downstream pro-inflammatory mediators. In addition to neuroprotection, minocycline treatment mitigated the cognitive impairment that appears to be a functional consequence of mu p75-SAP lesioning. The current study demonstrates that glial-related inflammation plays a significant role in the selective neurotoxicity of mu p75-SAP, and suggests that minocycline may provide a viable therapeutic option for degenerating cholinergic systems.

Publication types

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

MeSH terms

  • Alzheimer Disease / prevention & control
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cholinergic Fibers / drug effects
  • Cholinergic Fibers / pathology*
  • Disease Models, Animal
  • Gene Expression / drug effects
  • Immunohistochemistry
  • Immunotoxins / administration & dosage
  • Immunotoxins / toxicity*
  • Injections, Intraventricular
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / genetics
  • Macrophage Activation / drug effects
  • Male
  • Maze Learning / drug effects
  • Memory Disorders / pathology
  • Memory Disorders / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / metabolism
  • Minocycline / pharmacology*
  • N-Glycosyl Hydrolases / administration & dosage
  • N-Glycosyl Hydrolases / toxicity*
  • Nerve Degeneration / pathology
  • Nerve Degeneration / prevention & control
  • Neuroprotective Agents / pharmacology*
  • Plant Proteins / administration & dosage
  • Plant Proteins / toxicity*
  • Prosencephalon / drug effects
  • Prosencephalon / metabolism
  • Prosencephalon / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosome Inactivating Proteins, Type 1
  • Saporins
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Immunotoxins
  • Interleukin-1
  • Neuroprotective Agents
  • Plant Proteins
  • Ribosome Inactivating Proteins, Type 1
  • Tumor Necrosis Factor-alpha
  • N-Glycosyl Hydrolases
  • Saporins
  • Minocycline