Abstract
BackgroundRecent evidence has suggested that Alzheimer’s disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms. However, the brain region specificity of caspase-independent PCD in AD-associated neurodegeneration is unknown. We therefore used the transgenic CRND8 (TgCRND8) AD mouse model to explore whether the apoptosis inducing factor (AIF), a key mediator of caspase-independent PCD, contributes to cell loss in selected brain regions in the course of aging.ResultsIncreased expression of truncated AIF (tAIF), which is directly responsible for cell death induction, was observed at both 4- and 6-months of age in the cortex. Concomitant with the up-regulation of tAIF was an increase in the nuclear translocation of this protein. Heightened tAIF expression or translocation was not observed in the hippocampus or cerebellum, which were used as AD-vulnerable and relatively AD-spared regions, respectively. The cortical alterations in tAIF levels were accompanied by increased Bax expression and mitochondrial translocation. This effect was preceded by a significant reduction in ATP content and an increase in reactive oxygen species (ROS) production, detectable at 2 months of age despite negligible amounts of amyloid-beta peptides (Aβ).ConclusionsTaken together, these data suggest that AIF is likely to play a region-specific role in AD-related caspase-independent PCD, which is consistent with aging-associated mitochondrial impairment and oxidative stress.
Highlights
Recent evidence has suggested that Alzheimer’s disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms
Accumulation of amyloid β peptides (Aβ) in the cortex and hippocampus of Tg mice is accompanied by signs of oxidative stress We examined the Aβ load as a function of age in the cortex, hippocampus and cerebellum of Tg mice
In all brain regions, including the cerebellum, the difference was significant for the comparison between 9-month-old animals and all other ages for both Aβ1–40 and Aβ1–42 (Figure 1A and B)
Summary
Recent evidence has suggested that Alzheimer’s disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms. We used the transgenic CRND8 (TgCRND8) AD mouse model to explore whether the apoptosis inducing factor (AIF), a key mediator of caspase-independent PCD, contributes to cell loss in selected brain regions in the course of aging. Animal models of AD offer a unique opportunity to study the Neurodegeneration in age-associated dementia of the AD type is thought to involve neuronal cell loss by programmed cell death (PCD) [6,7]. Apoptosis-inducing factor (AIF) is considered to play a central role among key effectors involved in caspase-independent neuronal cell death [19,20,21]. We have recently reported the increased nuclear translocation of AIF in the hippocampus and cortex of post-mortem human tissues derived from AD patients [22]; this being indicative of caspaseindependent PCD via AIF
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