Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease

Glia. 2010 Feb;58(3):300-14. doi: 10.1002/glia.20924.


Alzheimer's disease (AD) is the most common progressive dementia and is pathologically characterized by brain deposition of amyloid-beta (Abeta) peptide as senile plaques. Inflammatory and immune response pathways are chronically activated in AD patient brains at low levels, and likely play a role in disease progression. Like microglia, activated astrocytes produce numerous acute-phase reactants and proinflammatory molecules in the AD brain. One such molecule, S100B, is highly expressed by reactive astrocytes in close vicinity of beta-amyloid deposits. We have previously shown that augmented and prolonged activation of astrocytes has a detrimental impact on neuronal survival. Furthermore, we have implicated astrocyte-derived S100B as a candidate molecule responsible for this deleterious effect. To evaluate a putative relationship between S100B and AD pathogenesis, we crossed transgenic mice overexpressing human S100B (TghuS100B mice) with the Tg2576 mouse model of AD, and examined AD-like pathology. Brain parenchymal and cerebral vascular beta-amyloid deposits and Abeta levels were increased in bigenic Tg2576-huS100B mice. These effects were associated with increased cleavage of the beta-C-terminal fragment of amyloid precursor protein (APP), elevation of the N-terminal APP cleavage product (soluble APPbeta), and activation of beta-site APP cleaving enzyme 1. In addition, double transgenic mice showed augmented reactive astrocytosis and microgliosis, high levels of S100 expression, and increased levels of proinflammatory cytokines as early as 7-9 months of age. These results provide evidence that (over)-expression of S100B acts to accelerate AD-like pathology, and suggest that inhibiting astrocytic activation by blocking S100B biosynthesis may be a promising therapeutic strategy to delay AD progression..

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Astrocytes / immunology
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cerebral Amyloid Angiopathy / genetics
  • Cerebral Amyloid Angiopathy / metabolism*
  • Cerebral Amyloid Angiopathy / physiopathology
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / genetics*
  • Gliosis / genetics
  • Gliosis / metabolism*
  • Gliosis / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / immunology
  • Microglia / metabolism
  • Microglia / pathology
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Protein Structure, Tertiary / physiology
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / genetics
  • S100 Proteins / metabolism*


  • Amyloid beta-Protein Precursor
  • Cytokines
  • Nerve Growth Factors
  • Peptide Fragments
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • S100B protein, human
  • S100b protein, mouse