Further Evidence on Mitochondrial Targeting of β-Amyloid and Specificity of β-Amyloid-Induced Mitotoxicity in Neurons

Abstract

Background/Aims: Impaired mitochondrial function has been described in Alzheimer’s disease. We previously reported that, in neuronal cells, β-amyloid 1–42 (Aβ_1–42) is targeted to mitochondria. We have also reported that, when incubated with isolated rat brain mitochondria, Aβ_1–42 inhibits complex IV, uncouples the mitochondrial respiratory chain, and promotes opening of the membrane permeability transition pore. Here, we further analyzed the targeting and mitotoxicity of Aβ_1–42. Methods and Results: Immunoelectron microscopy revealed that the mitochondrial targeting of Aβ_1–42 was concentration- and time-dependent. Incubation of human neuroblastoma cells with Aβ_1–42 increased the release of adenylate kinase, a mitochondrial enzyme released after membrane permeability transition pore opening. However, it failed to trigger DNA fragmentation and apoptosis, suggesting that the ability of this peptide to uncouple the respiratory chain underlies its mitotoxicity and cytotoxicity. Aβ_1–42 targeting to mitochondria was blocked by caprospinol, a steroid derivative shown to protect neuronal cells against Aβ_1–42-induced neurotoxicity. Further experiments revealed that the mitotoxic effect of Aβ_1–42 is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of Aβ_1–42 was not restricted to brain cells, indicating that it is not cell- or tissue-specific. Conclusion: Taken together, these results suggest that extracellular Aβ_1–42 targets neuronal mitochondria to exert its toxic effects.

Interaction of Aβ(25–35) fibrillation products with mitochondria: Effect of small‐molecule natural products

“…Release of MDH was measured upon interaction of mitochondrial suspensions (1 mg/ml) with 10 lM of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fibrillation products corresponding to 0 h (monomer), 24 h, 1 week, 2 weeks, 3 weeks, and 1 month of incubation. [72][73][74] Meanwhile, Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) has shown to significantly decrease the activity of CS and all respiratory chain complexes and cause a generalized loss of mitochondria in neurons. Data are expressed as mean 6 STD with n 5 6.…”

“…2,71 Accordingly, it has been suggested that Ab toxicity is mediated via effects on mitochondria. [72][73][74] Meanwhile, Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) has shown to significantly decrease the activity of CS and all respiratory chain complexes and cause a generalized loss of mitochondria in neurons. 75 We assumed that the increased surface hydrophobicity of Ab(25-35) peptide upon amyloid formation enhanced capability of the peptide to interact with the lipid bilayers, resulting in mitochondrial membrane disruption.…”

Not Oligomers but Amyloids are Cytotoxic in the Membrane‐Mediated Amyloidogenesis of Amyloid‐β Peptides

“…Tillement et al. reported that Aβ(1–42) accumulated in mitochondria and did not induce apoptosis even at 10 μ m , although Meng et al. observed Aβ‐induced apoptosis .…”

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

“…Aβ 1–42 peptides are imported into the mitochondria via the translocase of the outer membrane import machinery and localizes to mitochondrial cristae [107]. The translocation of Aβ 1–42 peptides into mitochondria has been linked to mitotoxic effects by in vitro and in vivo evidence, such as increased release of adenylate kinase and ROS, and this mitotoxicity is promoted by aging [108,109,110]. Calcium influx is one of the mitotoxic effects induced by Aβ 1–42 , and evidence suggests that oxidative stress and the subsequent neurodegeneration induced by accumulation of Aβ 1–42 peptides are calcium influx-dependent (Figure 2) [111,112,113].…”