Abstract
BackgroundInflammation 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.MethodsEarly 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.ResultsFoci 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-1β, 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, β-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 Aβ deposits.ConclusionThe 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.
Highlights
Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD)
Amyloid plaques were undetectable by Thioflavin-S or Aβ immunostaining in brains of amyloid precursor protein (APP) [V717I] mice at 3 months of age but were abundantly present in 16 month old transgenic mice (Fig. 1A)
Since we demonstrated that cytokine stimulated neuronal cells increased production of Aβ by transcriptional BACE1 up-regulation in vitro [18], and the latter cytokines were detectable at sites of early inflammation in young APP [V717I] mice, we analysed whether early inflammatory foci would be accompanied by BACE1 expression
Summary
Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD). Aβ peptides are generated from amyloid precursor protein (APP) by sequential actions of two proteolytic enzymes, i.e. the βsite APP cleavage enzyme (BACE1) and the γ-secretase [1,2] Their formation and eventual deposition represents a key feature and possibly the triggering mechanism of AD. The importance of Aβ formation was instigated by dominantly inherited familial forms of AD that are linked to APP mutations in or close to the β- and γ-secretase cleavage sites [3] This made it possible to generate transgenic mouse models of cerebral amyloidosis and AD-like histopathology, i.e. amyloid plaques and cerebral amyloid angiopathy (CAA) [4,5,6](3–8) [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
