(Press-News.org) Immediate-early genes (IEGs), including c-Fos, are integral to the brain's response to stimuli. Initially identified as a proto-oncogene, c-Fos is essential for neural activity, synaptic plasticity, and stress responses. While its transient expression supports memory formation in healthy brains, chronic overexpression in AD exacerbates neurotoxicity and cognitive decline. This review synthesizes findings from postmortem studies, animal models, and cell cultures to elucidate the dual roles of c-Fos and its mechanisms in AD pathogenesis.
Expression of c-Fos in Brain Regions and Cell Types
c-Fos is expressed in specific brain regions such as the hippocampus, amygdala, and cortex, mapping neural activity in response to stimuli. It is not limited to neurons; glial cells, including astrocytes and microglia, also exhibit c-Fos induction under stress or inflammation. In AD, glial c-Fos expression contributes to neuroinflammation and neuronal loss, mediated by pathways involving glutamate receptors and cytokines. This broad expression pattern underscores its role in both physiological and pathological states.
Roles of c-Fos in Learning and Memory
In healthy brains, c-Fos is crucial for memory consolidation and synaptic plasticity. Its expression peaks during novel experiences but diminishes with habituation, reflecting adaptive neural responses. Disruptions in c-Fos function impair long-term memory, as evidenced by studies using antisense oligonucleotides. The sensitivity of c-Fos to stimulus intensity and frequency further highlights its role in encoding and recalling memories.
Mechanisms of c-Fos Induction in Learning and Memory
c-Fos activation during learning involves glutamate signaling, NMDA receptors, and downstream kinases like ERK and CREB. These pathways culminate in the formation of the AP-1 transcription complex, which regulates genes such as Arc and BDNF, essential for synaptic plasticity. The biphasic regulation of c-Fos—acute induction followed by adaptation—ensures efficient memory formation while preventing overstimulation.
c-Fos in Alzheimer’s Disease
In AD, c-Fos expression is aberrantly elevated, correlating with amyloid-β (Aβ) accumulation and cognitive impairment. Aβ stabilizes c-Fos via O-GlcNAcylation, promoting apoptosis through AP-1 and ATF3. Chronic c-Fos activation disrupts synaptic function and exacerbates neuroinflammation, creating a vicious cycle of neurodegeneration. Studies in AD models reveal hippocampal hyperactivity and neuronal loss linked to c-Fos overexpression, suggesting its role in early disease markers.
Possible Mechanisms of c-Fos in AD
The pathological effects of c-Fos in AD stem from dysregulated calcium signaling, oxidative stress, and epigenetic modifications. Constitutive CREB activation and mitochondrial dysfunction further perpetuate neuronal damage. The inability of c-Fos to habituate to repeated stimuli in AD underscores its role in sustained neurotoxicity and synaptic degeneration.
c-Fos and Apoptosis in AD
c-Fos promotes apoptosis via ATF3 and pro-apoptotic genes like Bim and cytochrome c. In AD, this pathway is hyperactivated, leading to widespread neuronal death. The ERK/FOS axis also intensifies inflammatory responses, highlighting c-Fos as a mediator of both apoptosis and neuroinflammation.
Oxidative Stress and c-Fos Expression in AD
Oxidative stress in AD activates MAPK pathways, upregulating c-Fos and disrupting mitochondrial function. This exacerbates ROS production and inflammatory cytokine release, further damaging neurons. The interplay between oxidative stress and c-Fos underscores its central role in AD progression.
Conclusions
c-Fos exhibits a dual role: supporting memory in healthy brains and driving neurodegeneration in AD. Its dysregulation in AD involves multiple pathways, including Aβ toxicity, apoptosis, and oxidative stress. Targeting c-Fos modulation offers promising therapeutic avenues to mitigate cognitive decline. Future research should explore c-Fos-specific interventions to disrupt its pathological effects while preserving its physiological functions.
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The study was recently published in the Gene Expression.
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