Abstract
We have previously shown that transgenic mice carrying a mutant human APP but deficient in CD40L, display a decrease in astrocytosis and microgliosis associated with a lower amount of deposited Aβ. Furthermore, an anti-CD40L treatment causes a diminution of Aβ pathology in the brain and an improved performance in several cognitive tasks in the double transgenic PSAPP mouse model. Although these data suggest a potential role for CD40L in Alzheimer's disease pathology in transgenic mice they do not cast light on whether this effect is due to inhibition of signaling via CD40 or whether it is due to the mitigation of some other unknown role of CD40L. In the present report we have generated APP and PSAPP mouse models with a disrupted CD40 gene and compared the pathological features (such as amyloid burden, astrocytosis and microgliosis that are typical of Alzheimer's disease-like pathology in these transgenic mouse strains) with appropriate controls. We find that all these features are reduced in mouse models deficient for CD40 compared with their littermates where CD40 is present. These data suggest that CD40 signaling is required to allow the full repertoire of AD-like pathology in these mice and that inhibition of the CD40 signaling pathway is a potential therapeutic strategy in Alzheimer's disease.
Highlights
The extracellular deposition of the amyloid β-peptide (Aβ) in senile plaques and intracellular accumulation of neurofibrillary tangles are the main pathological features of Alzheimer's disease (AD) [1]
Previous in vitro work shows that Aβ-induced microglial activation is greatly enhanced by stimulation of the CD40 pathway, and that secretion of tumor necrosis factor alpha and neuronal death occur when Aβ-treated microglia are challenged with CD40 ligand, CD40L [3]
It has previously been shown that reduction of functional CD40L mitigates AD like-pathology in transgenic mouse models of AD [3,7]
Summary
The extracellular deposition of the amyloid β-peptide (Aβ) (which is derived from the processing of the amyloid precursor protein [APP]) in senile plaques and intracellular accumulation of neurofibrillary tangles (principally composed of phosphorylated tau protein) are the main pathological features of Alzheimer's disease (AD) [1] Besides these lesions, a continuous inflammatory state exists in the brain of AD patients associated with a secretion of pro-inflammatory cytokines around amyloid deposits. Previous in vitro work shows that Aβ-induced microglial activation is greatly enhanced by stimulation of the CD40 pathway, and that secretion of tumor necrosis factor alpha and neuronal death occur when Aβ-treated microglia are challenged with CD40 ligand, CD40L [3]. The pattern (page number not for citation purposes)
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