In mice fed a diet high in fat and carbohydrates, activation of specific cellular signaling pathways in the hippocampus is linked to increased inflammation and damage to nerve cells, which may...
Mechanism
Synthesis from 1 study
Eating too much fat and sugar changes gut bacteria, which damages mitochondria and causes their DNA to leak into brain cells. This leaked DNA triggers two immune alarms that turn on inflammation, killing nerve cells in the memory center and making it harder to learn and remember things.
Most probable mechanism
Eating a lot of fat and sugar changes the gut bacteria, causing the gut lining to become leaky. This lets bacterial toxins enter the bloodstream, which damages mitochondria in cells throughout the body, including the brain. When mitochondria are damaged, their DNA escapes into the cell's main compartment. This free DNA is recognized as dangerous by two immune sensors inside brain cells, which turn on powerful inflammation signals. These signals cause brain immune cells to become overactive, releasing chemicals that harm and kill nearby nerve cells in the memory center of the brain, leading to trouble with learning and remembering.
A high-fat, high-carbohydrate diet alters the composition of gut microbiota, reducing beneficial species and increasing pro-inflammatory bacterial strains
Dysbiosis increases intestinal permeability, allowing microbial products such as lipopolysaccharide to enter systemic circulation
Systemic microbial toxins induce mitochondrial stress and reduce expression of TFAM, a key regulator of mitochondrial DNA maintenance
Mitochondrial damage causes mitochondrial DNA to be released into the cytosol of peripheral and central nervous system cells
Cytosolic mitochondrial DNA is detected by the AIM2 inflammasome, triggering assembly of a complex that activates caspase-1 and cleaves pro-inflammatory cytokines IL-1β and IL-18 into their active forms
Cytosolic mitochondrial DNA also binds to cGAS, which synthesizes cyclic GMP-AMP to activate STING, leading to phosphorylation of IRF3 and production of type I interferons
Active IL-1β, IL-18, and type I interferons cross the blood-brain barrier or activate resident microglia and astrocytes, initiating chronic neuroinflammation
Sustained neuroinflammatory signaling activates intrinsic apoptotic pathways in hippocampal neurons, resulting in progressive neuronal loss
Loss of hippocampal neurons and disruption of synaptic networks impair memory formation and cognitive function
Evidence from Studies
Supporting (1)
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