In older mice, deficiency of Nipsnap1, a mitochondrial protein that helps clear damaged mitochondria, shifts the brain from synaptic activity toward inflammation resembling early Alzheimer’s disease and leads to memory loss
In older mice, deficiency of Nipsnap1, a mitochondrial protein that helps clear damaged mitochondria, shifts the brain from synaptic activity toward inflammation resembling early Alzheimer’s disease and leads to memory loss
Biologists compared older mice (15 months, an advanced age for a laboratory mouse) with a congenital deficiency of the Nipsnap1 gene against normal mice of the same age, examining gene activity, mitochondrial biochemistry, cell death, and memory. Mice deficient in Nipsnap1 showed a sharp increase in inflammatory gene activity and greater activation of microglia, the brain’s immune cells. Synaptic gene activity declined, mitochondrial energy metabolism became disrupted, and memory was poorer. These effects occurred predominantly in females.
Nipsnap1 is a small protein inside mitochondria, the structures that supply cells with energy. It helps identify damaged mitochondria and initiates their breakdown through a process called mitophagy. A recognizable region of the protein has remained almost unchanged across more than 2200 species, from bacteria to humans. In the brain, the protein is particularly active in neurons. Scientists have only now examined what its deficiency does to the aging brain, in a paper published on October 6.
In 2010, the same laboratory found that Nipsnap1 physically binds to amyloid precursor protein (APP), the protein from which toxic plaques form in the brain in Alzheimer’s disease. That finding led to the current experiment.
RNA sequencing of the cerebral cortex revealed a pronounced shift: 1538 synaptic genes were downregulated, while 1596 genes involved in inflammation and innate immunity were upregulated, including Trem2, ApoE, and complement genes. The same set of genes is used to identify inflammatory microglia in Alzheimer’s disease. Brain sections showed fewer neurons and more activated microglia.
Isolated mitochondria showed a paradoxical pattern: production of ATP, the cell’s energy currency, increased slightly, but so did production of reactive oxygen species, which damage cells. Meanwhile, the ratio of NAD⁺ to NADH, an indicator of how well energy metabolism is functioning, fell. Analysis of brain metabolism suggested a possible explanation: a product of DNA repair increased almost ninefold, a sign that the enzyme PARP was continuously consuming cellular NAD⁺ to repair DNA damage. In females, brain cell death was already elevated at one month of age, long before old age.
In the novel object recognition test, healthy mice spend longer exploring a new object. Mice deficient in Nipsnap1 spent longer exploring the familiar object, as though they did not remember seeing it before. They also performed substantially worse than controls in a maze that tests short-term spatial memory.
Nearly all the effects occurred in females. Males with the same deficiency showed smaller changes or changes that were not statistically significant. Only the reduction in the mitochondrial NAD⁺/NADH ratio was equally pronounced in both sexes.
The authors bring these findings together in a model: Nipsnap1 deficiency disrupts mitochondrial energy metabolism, which damages neurons and synapses. The microglial response then compounds the damage, together leading to neuronal loss and memory impairment. These mice lack the protein from birth, so its absence precedes aging. The result therefore demonstrates that this congenital deficiency alone is sufficient to produce an aged brain phenotype.
An earlier study in 2025, in which both the Nipsnap1 and Nipsnap2 genes were completely deleted in mice, had already shown accelerated aging throughout the body, including muscle weakness and inflammation in the heart, liver, and kidneys. That study did not examine the brain. The new paper is the first to link Nipsnap1 loss to effects on the brain and memory.