Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice

Neurosci Lett. 2009 Mar 27;453(1):41-4. doi: 10.1016/j.neulet.2009.01.075. Epub 2009 Feb 4.


Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid-beta protein in the aged brain. Inefficient clearance of amyloid-beta from brain tissue is believed to play a major role in the pathogenesis of these deposits. Since amyloid-beta clearance likely involves activation of microglial cells via toll-like receptors and since these receptors and their signaling pathways are regarded as potential therapeutic targets, we have studied the expression of toll-like receptor (tlr) mRNAs in an animal model of AD (APP23 transgenic mice). Laser microdissection was used to harvest plaques, tissue surrounding plaques and plaque-free tissue from cortex of aged APP23 transgenic mice and age-matched controls. Real-time RT-PCR was employed to quantify expression levels of different tlr mRNAs in these tissues. This revealed a strong upregulation of tlr2, tlr4, tlr5, tlr7 and tlr9 mRNAs in plaque material compared to plaque-free tissue. In contrast, tlr3 was not significantly upregulated. Plaque-free tissue did not show an increased expression of any tlr mRNAs compared to age-matched control mice. Double-immunofluorescence for TLR2 and the microglial marker Iba1 was used to demonstrate localization of TLR2 on plaque-associated microglia. Taken together, these data show a strong upregulation of mRNAs encoding surface TLRs in plaque-associated brain tissue of aged APP23 transgenic mice. Since TLR-upregulation is restricted to plaques, modifying TLR-signaling may be a promising therapeutic strategy for plaque removal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Alzheimer Disease / metabolism*
  • Animals
  • Calcium-Binding Proteins / metabolism
  • Cerebral Cortex / metabolism*
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins
  • Microglia / physiology
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / metabolism
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism*
  • Up-Regulation


  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Membrane Glycoproteins
  • Microfilament Proteins
  • RNA, Messenger
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Tlr7 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors