Dynamic interplay of cellular senescence, chronic neuroinflammation and synaptic plasticity in age-related neurodegeneration

The nervous system, as the organ responsible for sensory information processing and motor control, executes advanced functions such as language, learning, cognition, and emotion. Cellular senescence, neuroinflammation, and synaptic plasticity decline in the central nervous system (CNS) constitute core pathological mechanisms underlying neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS) etc. Senescent neurons and glial cells secrete pro-inflammatory cytokines and reactive oxygen species (ROS), which amplify neuroinflammatory responses, accelerate cellular senescence, and disrupt synaptic homeostasis. Neuroinflammation directly eliminates synapses or inhibits synaptic plasticity-related molecules via immune signaling pathways and complement activation. Concurrently, synaptic dysfunction exacerbates metabolic dysregulation and pathological protein propagation, further driving neuronal senescence and inflammatory amplification, forming a self-reinforcing vicious cycle. Although AD, PD and MS exhibit distinct pathological features and regional brain involvement, both adhere to a tripartite pathological framework centered on "senescence-inflammation-synaptic damage". This review systematically explores the multidimensional impact of CNS aging, dissects the driving role of neuroinflammation, and highlights the pivotal position of synaptic plasticity decline in disease progression. These insights provide a scientific foundation for developing unified theoretical models of neurodegenerative diseases and multi-target therapeutic strategies.