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- W1970197209 abstract "A primary focus of Alzheimer's disease (AD) research has been to elucidate the relationship between beta amyloid (Aβ) and neurite degeneration; yet, it remains unknown why AD affects primarily the elderly. We have previously described a process of neurite degeneration involving Aβ-dependent calpain activation, resulting in the generation of a neurotoxic 17 kDa tau fragment in mature cultured hippocampal neurons. However, the potential developmental regulation of this process has not been investigated. Therefore, we analyzed to what extent Aβ toxicity differs in neurons of different developmental stages, and whether membrane cholesterol, a potential player in AD pathology, may mediate these differences. Seven (young) and 21 (mature) days in culture hippocampal neurons were cultured in the absence or presence of 10 μM pre-aggregated Aβ1–40 for 24 hours. We used immunocytochemistry and immunoblotting to detect Aβ-induced neurodegenerative morphology and 17 kDa tau production, respectively. Aβ-dependent calpain activity in these lysates was measured by immunoblotting for cleaved spectrin as well as by a calpain activity assay. Membrane cholesterol was detected in young and mature neurons via filipin labeling and the Amplex Red cholesterol assay to assess the potential mediatory role of cholesterol in these mechanisms of Aβ toxicity. To determine whether low cholesterol in young neurons was protective against Aβ-induced calpain activation and toxicity, we repeated the aforementioned experiments in mature neurons depleted of cholesterol using methyl-β-cyclodextrin (MBCD). Aβ treatment induced neurodegenerative morphology and 17 kDa tau production only in mature neurons as compared to young ones. Our results also demonstrated that 17 kDa tau production is regulated by elevated calpain activity. These age-dependent changes in Aβ-induced calpain activity were accompanied by an age-dependent increase in neuron membrane cholesterol; thus, suggesting that mediatory components of this neurodegenerative process likely lie upstream of calpain. Concurringly, MBCD treatment of mature neurons significantly reduced their vulnerability to Aβ-induced calpain activation and 17 kDa tau production under these experimental conditions. Together, these results revealed an age-dependent increase in susceptibility of hippocampal neurons to Aβ-induced calpain-mediated 17 kDa tau production and degeneration. Furthermore, they identified membrane cholesterol as a potential mediator of these mechanisms." @default.
- W1970197209 created "2016-06-24" @default.
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- W1970197209 date "2008-07-01" @default.
- W1970197209 modified "2023-10-06" @default.
- W1970197209 title "P3-341: Increased membrane cholesterol may render mature hippocampal neurons more susceptible to beta-amyloid-induced calpain activation and tau toxicity" @default.
- W1970197209 doi "https://doi.org/10.1016/j.jalz.2008.05.1910" @default.
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