Amyloid β‑42 induces neuronal apoptosis by targeting mitochondria.

Alzheimer's disease (AD), with a typical pathological hallmark of amyloid‑beta (Aβ)‑containing plaques and neurofibrillary tangles, is one of the most common types of chronic neurodegenerative diseases. Aβ oligomers serve a crucial role in the pathogenesis of AD, and lead to neuronal loss. However, the precise mechanism of Aβ oligomers in AD remains to be elucidated. The present study demonstrated that 10 μM Aβ‑42 activated the caspase signaling pathway, and induced significant apoptosis in primary cultured mouse cerebral cortical neurons. The results of reverse transcription‑quantitative polymerase chain reaction and western blotting demonstrated that Aβ‑42 (10 μM) also significantly upregulated the transcription and expression of the mitochondrial fission protein dynamin‑related protein 1 (Drp1), and downregulated the transcription and expression of mitochondrial fusion proteins, including mitofusin 1/2 (Mfn1/2) and mitochondrial dynamin like GTPase (OPA‑1). Neurons were transfected with pDsRed2‑Mito for mitochondrial imaging, which revealed that 10 μM Aβ‑42 induced mitochondrial fission in cortical neurons. In addition, 2',7'‑dichlorodihydrofluorescein diacetate and tetramethylrhodamine ethyl ester staining indicated that Aβ‑42 increased the reactive oxygen species (ROS) level and reduced mitochondrial membrane potential in neurons. Inhibition of Drp1 activity by Mdivi‑1 efficiently prevented Aβ‑42‑induced ROS production and disruption of mitochondrial membrane potential. Loss of mitochondrial membrane potential may activate PTEN‑induced putative kinase 1 (Pink1), the prominent sensor for mitochondrial damage, and trigger the process of mitophagy to remove the damaged mitochondria. In the present study, western blotting revealed that the levels of autophagy marker microtubule‑associated proteins 1A/1B light chain 3B (LC3B) and Pink1 were upregulated after Aβ‑42 stimulation. In conclusion, these data indicated that Aβ‑42 induces neuronal apoptosis by targeting mitochondria, including promotion of mitochondrial fission, disruption of mitochondrial membrane potential, increasing intracellular ROS level and activation of the process of mitophagy. Therefore, mitochondria may represent a potential therapeutic target for AD in the future. [ABSTRACT FROM AUTHOR]