Fas and Fas Ligand are associated with neuritic degeneration in the AD brain and participate in β-amyloid-induced neuronal death

• Main Authors: Joseph H Su, Aileen J Anderson, David H Cribbs, Christina Tu, Liqi Tong, Patrick Kesslack, Carl W Cotman
• Format: Article
• Language: English
• Published: Elsevier 2003-04-01
• Series: Neurobiology of Disease
• Subjects: Fas; FasL; Senile plaques; β-Amyloid; Dystrophic neurites; Apoptosis
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996102000190

It has recently been suggested that neuronal cell death in response to many brain insults may be mediated by the upregulation of tumor necrosis factor receptor (TNFR) family members and their ligands. In the present study, we investigated whether the expression of the TNFR family death domain receptor, Fas, and its ligand, FasL, is altered in association with neuropathology and activated caspase markers in Alzheimer disease (AD) brain, and Aβ-induced neuronal cell death in vitro. To evaluate this hypothesis, we examined Fas and FasL expression in AD and control brain, and Aβ-treated primary neurons, using immunocytochemistry and Western blots. Neurons in both AD brain and Aβ-treated cultures exhibited FasL upregulation and changes in immunoreactivity for Fas receptor. Further, FasL expression was remarkably elevated in senile plaques and neurofilament-positive dystrophic neurites, and in association with caspase activation and neuritic apoptosis in AD brain. Based on these and previous data regarding protection of primary neuronal cultures from Aβ1–42-induced apoptosis by blockade of Fas-associated death domain signaling, we also tested the hypothesis that dynamic regulation of Fas and FasL may contribute to Aβ-mediated neuronal cell death. Accordingly, neuronal cultures derived from mice carrying inactivating mutations in Fas (Faslpr) or FasL (Fasgld) exhibited protection from Aβ1–42-induced cell death. These findings suggest that Fas–FasL interactions may contribute to mechanisms of neuronal loss and neuritic degeneration in AD.