Experimental Neurology最新文献

The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurodegeneration. While their co-occurrence is established, causal relationships remain poorly understood-a critical gap for developing mechanism-based therapies rather than symptomatic treatments. This review examines evidence for causality among glial senescence, neuroinflammation, and neurodegeneration using Bradford Hill criteria, longitudinal studies, genetic approaches, and senolytic trials. Glial senescence in astrocytes and microglia initiates neuroinflammatory cascades through the senescence-associated secretory phenotype (SASP), creating self-perpetuating cycles driving neuronal dysfunction. However, neuroinflammation also emerges as a primary event triggered by peripheral signals, blood-brain barrier breakdown, or pathogens, subsequently inducing glial senescence. Neuronal damage generates inflammatory signals activating glia, indicating bidirectional causality. Disease-specific patterns are heterogeneous: in Alzheimer's disease, early microglial activation may precede amyloid pathology, while in Parkinson's disease, gut-brain inflammation may initiate central pathology. Common feed-forward loops amplify initial insults-senescence, inflammation, or protein aggregation-transcending linear causality. We propose a framework recognizing critical temporal windows and tipping points, distinguishing reversible from irreversible stages. Anti-inflammatory and senolytic interventions show promise preventively or early but limited efficacy in advanced disease, emphasizing intervention timing. Outstanding questions include identifying earliest causal events, determining points of no return, and understanding genetic-environmental modification of causal pathways. Addressing these requires longitudinal multi-omics studies and interventional trials. Establishing causation beyond correlation enables precision medicine targeting root causes, offering hope for preventing age-related cognitive decline and neurodegeneration.

This review systematically summarizes the mechanisms of 40 Hz gamma rhythm neuromodulation and its research advances in neurological disorders. As a key rhythm for brain information integration, 40 Hz gamma oscillations are generated by the interaction between excitatory and inhibitory neurons, and play a central role in cognitive functions such as attention and memory. They are commonly characterized by decreased power or loss of synchrony in various diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia, serving as a shared electrophysiological hallmark. Extrinsic 40 Hz stimulation (e.g., transcranial alternating current stimulation, light flickering, acoustic stimulation) can restore endogenous gamma rhythms through the entrainment effect, improve excitation-inhibition balance, enhance synaptic plasticity, and promote the clearance of pathological proteins by activating microglia and other mechanisms. Clinical studies have shown that this technology improves cognitive, emotional, and motor functions, with advantages of non-invasiveness and high safety. Despite challenges such as individual variability, marked methodological heterogeneity (e.g., inconsistent stimulation parameters, small sample sizes, and lack of multicenter randomized controlled trials), and unclear long-term effects, 40 Hz neuromodulation still demonstrates broad therapeutic potential and provides a novel rhythmic intervention strategy for neurological disorders.

The progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) due to the aggregation of Lewy bodies is the hallmark of Parkinson's disease (PD). ROS play a key role in the formation of Lewy bodies, thus leading to mitochondrial dysfunction and the apoptosis of neurons. A rotating magnetic field (RMF) is an emerging noninvasive technique for the prevention of neurodegenerative disorders. To investigate the potential therapeutic effects of RMS in PD, we subjected an experimental mouse model to RMF. CblC mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg, i.p., once daily for 5 days), followed by RMF treatment at a frequency and intensity of 4 Hz and 0.4 T, respectively. The daily 2-h RMF treatment was continued for a period of 6 months. We examined the effects of RMF on motor functions, the aggregation of Lewy bodies and the integrity and viability of total and dopaminergic neurons in the SNpc and striatal regions. We further performed transcriptomic analysis of SNpc tissue from PD and SHAM mice. Our results showed that exposure to RMF improved motor functions, enhanced neuronal cell viability and protected neuronal integrity in a PD mouse model. We further showed that RMF diminishes the number of aggregated Lewy bodies in neurons and reduces ROS production. Overall, the results of the transcriptomic analysis revealed that RMF promoted the expression of anti-apoptotic genes rather than proapoptotic genes that are specifically involved in mitochondrial apoptosis.