title: Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice.
abstract: BACKGROUND
  Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD). Transgenic mice overexpressing the london mutant of amyloid precursor protein, APP [V717I], robustly recapitulate the amyloid pathology of AD.
  
  
  METHODS
  Early and late, temporal and spatial characteristics of inflammation were studied in APP [V717I] mice at 3 and 16 month of age. Glial activation and expression of inflammatory markers were determined by immunohistochemistry and RT-PCR. Amyloid deposition was assessed by immunohistochemistry, thioflavine S staining and western blot experiments. BACE1 activity was detected in brain lysates and in situ using the BACE1 activity kit from R&D Systems, Wiesbaden, Germany.
  
  
  RESULTS
  Foci of activated micro- and astroglia were already detected at age 3 months, before any amyloid deposition. Inflammation parameters comprised increased mRNA levels coding for interleukin-1beta, interleukin-6, major histocompatibility complex II and macrophage-colony-stimulating-factor-receptor. Foci of CD11b-positive microglia expressed these cytokines and were neighbored by activated astrocytes. Remarkably, beta-secretase (BACE1) mRNA, neuronal BACE1 protein at sites of focal inflammation and total BACE1 enzyme activity were increased in 3 month old APP transgenic mice, relative to age-matched non-transgenic mice. In aged APP transgenic mice, the mRNA of all inflammatory markers analysed was increased, accompanied by astroglial iNOS expression and NO-dependent peroxynitrite release, and with glial activation near almost all diffuse and senile Abeta deposits.
  
  
  CONCLUSIONS
  The early and focal glial activation, in conjunction with upregulated BACE1 mRNA, protein and activity in the presence of its substrate APP, is proposed to represent the earliest sites of amyloid deposition, likely evolving into amyloid plaques.
authors.affiliation: Department of Neurology, University of Münster, 48149 Münster, Germany. heneka@uni-muenster.de
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sastre
authors.forename: Lucia
authors.initials: L
authors.lastname: Dumitrescu-Ozimek
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven