Aging exacerbates PD pathology through mitochondrial dysfunction and neuroinflammation (IMAGE)
Caption
(1) Mitochondrial failure, where aging reduces compensatory mtDNA replication, leads to ROS accumulation, respiratory chain damage (NADH/CoQ deficiency), and membrane potential collapse. These defects impair ATP production while increasing oxidative damage to lipids/proteins.
(2) α-Synuclein aggregation is amplified by aging microglia through TREM2 down-regulation and TLR/NF-κB/NLRP3 activation, which promotes the release of inflammatory factor (e.g., IL-1β and TNF-α) and JNK/AP-1 pathway-mediated neuronal stress.
(3) Astrocyte senescence, driven by the cGAS–STING–IRF3 axis and LCN2 up-regulation, creates a neurotoxic environment via endoplasmic reticulum stress and diminished antioxidant defenses (SOD/GPx/GSH depletion). Collectively, these processes form a vicious cycle: mitochondrial OXPHOS fragmentation and calcium dyshomeostasis accelerate neuronal damage, while microglial/astrocytic inflammation further propagates α-synuclein pathology, ultimately driving dopaminergic neurodegeneration
Credit
Tingting Liu, Jingwen Li, Haojie Wu, Junbo Qiao, Jianshe Wei
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CC BY-NC-ND