The expression of apoptosis inducing factor (AIF) is associated with aging-related cell death in the cortex but not in the hippocampus in the TgCRND8 mouse model of Alzheimer’s disease

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.

Protective Effects of Colivelin Against Alzheimer's Disease in a PDAPP Mouse Model

“…In brain of AD patients, cell apoptosis is an important feature which contributes to memory dysfunction and tissue damages [21,22]. We found that CLN effectively inhibited cell apoptosis in brain of AD mice.…”

Changes in PPARδ expression in a rat model of stress‐induced depression

“…26 Recent research has demonstrated that the PPARβ/δ agonists possess antiapoptotic properties in vitro, which may underlie their neuroprotective potential in vivo. 23 Our in vivo study showed that AIF and caspase-3 levels in the hippocampus were markedly increased, but Bcl-2 expression was decreased after the CMS procedure or after PPARδ was silenced in normal rats, which exhibited depression-like responses. Therefore, these results suggest that the antidepressant-like effect of PPARδ appears to be associated with its anti-apoptosis action.…”

“…It has been established that the external stress‐induced pathways can initiate a cascade of events that leads to a reduction in synaptic connection and a deficit in neuronal function . The nuclear translocation of AIF has been considered to be a major mechanism in neurodegenerative diseases . Caspase‐independent AIF nuclear translocation appears to be mediated by the cleavage by cysteine proteases such as cathepsins and calpains, which are different from caspases; this is usually a very early event in the cell death cascade.…”

“…21 The nuclear translocation of AIF has been considered to be a major mechanism in neurodegenerative diseases. 23 Caspase-independent AIF nuclear translocation appears to be mediated by the cleavage by cysteine proteases such as cathepsins and calpains, which are different from caspases; 24 this is usually a very early event in the cell death cascade. Moreover, the nuclear translocation of AIF requires caspase-3 activation, which is also Bcl-2 dependent.…”

Effects of rhein lysinate on D-galactose-induced aging mice

“…An excess of ROS can result in cell aging and death (1,2,4). Numerous studies have discovered that oxidative stress occurs during the pathogenesis of age-associated diseases (4)(5)(6)(7)(8).…”