In C57BL/6 mice, a diet high in fats and carbohydrates is associated with lower levels of TFAM protein, higher levels of mitochondrial DNA in the cell cytoplasm, and activation of innate immune...
Mechanism
Synthesis from 1 study
Too much fat and sugar changes gut bacteria, which causes toxins to leak into the blood and damage the energy parts of cells. This makes mitochondrial DNA escape into the wrong part of the cell, tricking the immune system into starting a long-lasting inflammatory response in the brain. That...
Most probable mechanism
Eating a lot of fat and sugar changes the gut bacteria, which makes the gut leaky and lets harmful substances into the bloodstream. These substances damage the energy factories inside cells, causing them to lose control of their DNA. Some of this DNA escapes into the cell's main compartment, where it tricks the immune system into thinking there's an infection. This triggers a strong inflammatory response that spreads to the brain, killing nerve cells in the memory center and making it harder to think clearly.
Consumption of a high-fat, high-carbohydrate diet alters the composition of gut microbiota, reducing beneficial species and increasing pro-inflammatory microbial strains
Dysbiosis increases intestinal permeability, allowing microbial products such as lipopolysaccharide to enter systemic circulation
Systemic microbial products induce mitochondrial stress in peripheral and central nervous system cells, suppressing expression of TFAM, a key regulator of mitochondrial DNA maintenance
Reduced TFAM leads to mitochondrial instability and release of mitochondrial DNA into the cytosol
Cytosolic mitochondrial DNA is recognized by cytosolic DNA sensors cGAS and AIM2, activating STING and inflammasome pathways respectively
Activation of cGAS-STING and AIM2 pathways triggers production of type I interferons and pro-inflammatory cytokines including IL-1β and IL-18
Inflammatory mediators cross the blood-brain barrier or activate resident microglia and astrocytes, initiating neuroinflammation
Chronic neuroinflammation induces intrinsic apoptotic signaling in hippocampal neurons, resulting in neuronal loss
Loss of hippocampal neurons disrupts synaptic plasticity and neural circuit function, impairing memory formation and cognitive performance
Evidence from Studies
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