Paraptosis triggers mitochondrial pathway-mediated apoptosis in Alzheimer's disease

Abstract

Abstract. In previous years, increasing evidence has indicated that paraptosis and mitochondrial-mediated apoptosis may be associated with Alzheimer's disease (AD). However, the association between paraptosis and mitochondrial-mediated apoptosis, and the pathological processes underlying AD, remain elusive. In the present study, the β-amyloid precursor protein gene, and the gene mutations PS1M146L and L286V, were transfected to an SH-SY5Y cell line to establish an AD cell model. Subsequently, an MTT assay was used to examine the cell viability of the AD cell model, while a TUNEL assay was employed to observe the number of positively stained apoptotic cells. Cytoplasmic vacuolization was examined using light microscopy and images were photographed. Furthermore, western blot analysis was utilized to detect the expression of golden biomarkers of the mitochondrial pathway, including Bcl-2 and Bax. The paraptosis inhibitor, cycloheximide, was selected to treat the AD model cells in order to observe the association between paraptosis and mitochondrial-mediated apoptosis. The results indicated that the decrease in the cell viability of the AD cells was initiated at 24 h, as compared with the normal cells (P<0.05). TUNEL-positive stained cells were observed at 48 h, which was later compared with the cell death initiation. In addition, examination of cytoplasmic vacuolization using microscopy indicated that there were a small number of paraptosis cells present at 24 h. The expression levels of Bcl-2 was significantly decreased, while Bax was significantly increased at 48 h. Furthermore, cycloheximide treatment was demonstrated to significantly increase Bcl-2 expression, while decreasing Bax expression (P>0.05). In conclusion, the occurrence of paraptosis was demonstrated in the early pathological stages of AD, which may subsequently damage the mitochondria and trigger mitochondrial pathway-mediated apoptosis. Thus, paraptosis may trigger programmed cell death directly, or indirectly through the regulation of Bcl-2 and Bax protein expression.

Programmed cell death in spinal cord injury pathogenesis and therapy

“…107 In Alzheimer's disease, a previous study found that paraptosis was demonstrated in the early pathological stages of Alzheimer's disease, which might do harm to the mitochondria and lead to mitochondrial pathway-mediated apoptosis, subsequently. 108 Furthermore, activated microglia can cause neuronal cell death with characteristic vacuolation following blocking the caspase cascade. 109 Microglia are known as a key component of the protective scar that forms after SCI, so in-depth study on the role of activated microglia in paraptosis should be an interesting new direction.…”

Multifunctional Heterometallic IrIII−AuI Probes as Promising Anticancer and Antiangiogenic Agents

“…Moreover, paraptosis is an independent caspases mechanism that displays mitochondrial swelling and produces cytoplasmatic vacuolation mainly derived from endoplasmic reticulum [39,40] . Despite several of these characteristics are in agreement with our observations, we identified cellular blebbing and apoptotic bodies in microscopy evaluation (black arrows in Figures S20 and S21) as well as annexin V labelling in flow cytometry analysis at 48 h of treatment but not at 24 h. Similarly, a study with an Alzheimer's disease cell model showed the presence of paraptotic cells at 24 h and with an increase in culture time, the presence of apoptotic cells after 48 h. In addition, a decrease in the expression levels of Bcl‐2 and Bax overexpression was observed at 48 and 72 h, suggesting that paraptosis finally unleashes mitochondrial apoptotic pathway [41] . Therefore, in the present case, it can be concluded that complexes 1 and 4 mediate paraptosis with subsequent apoptotic cell death.…”

Solute carrier 41A3 encodes for a mitochondrial Mg2+ efflux system

“…In particular, diseases that belong to hereditary or age-related mitopathies have been demonstrated to be characterized by aberrant mitochondrial homeostasis and the consequent loss of control over cellular energy turnover (e.g., Alzheimer’s and Parkinson´s diseases, diabetes mellitus type 2, schizophrenia). Furthermore, these diseases are often associated with Mg deficiency 36 37 38 39 40 41 42 . To date, the mitochondrial Mg 2+ channel Mrs2 is the only transport mechanism that might link Mg deficiency with disturbed mitochondrial homeostasis 43 .…”