Mice subjected to prolonged, low-level stress showed an increase in neurofibrillary tangles.

Subjecting mice to repeated emotional stress may contribute to the accumulation of neurofibrillary tangles, one of the hallmarks of Alzheimer’s disease, report researchers at the Salk Institute for Biological Studies. The group’s findings suggest that the brain-damaging effects of negative emotions are relayed through the two known corticotropin-releasing factor receptors, CRFR1 and CRFR2, which are part of the body’s response to stress and stress-related disorders.

Restraining mice for half an hour, a situation that replicates the body’s reaction to low-level anxiety, fear, or social stress, resulted only in a transient phosphorylation of tau protein. However, when chronic stress was simulated by repeating the procedure every day for two weeks, the modification lasted long enough to let tau molecules tumble off the cytoskeleton and pile up in insoluble heaps of protein.

After ruling out glucocorticoids, the next obvious candidate was the CRF system. The researchers then studied mice that had been genetically engineered to lack either CRFR1 or CRFR2 and found that in the absence of CRFR1, stress-induced tau phosphorylation was abrogated, while in mice missing CRFR2 the effect was amplified. Pharmacological studies with small molecule inhibitors replicated the effect.

Recently, researchers have also documented that CRF increases levels of amyloid beta, a protein involved in Alzheimer’s, in mice exposed to low-level stress.  

The results are detailed in the Journal of Neuroscience.

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