Salk Institute for Biological Studies: InsideSalk

A Possible Mechanistic Link Between Stress and Development of Alzheimer's Tangles

Aging is the greatest risk factor for Alzheimer's disease, but evidence suggests that emotional stress may also contribute to accumulation of neurofibrillary tangles, a hallmark of that condition.

Paul Sawchenko, professor in the Neuronal Structure and Function Laboratory, showed in the Journal of Neuroscience that damage triggered by negative emotions is relayed through two receptors expressed by certain brain cells, CRFR1 and CRFR2, to modulate a key process in the development of Alzheimer's neuropathology.

In Alzheimer's disease, a protein called tau becomes overly decorated with small chemical modifiers called phosphate groups. Hyper-phosphorylated tau then becomes insoluble within nerve cells, contributing to cell death.

In their study, Sawchenko and senior research associate Robert Rissman stressed mice by physically restraining them just once for 30 minutes and observed marked, but short-lived, increases in tau phosphorylation in the brain's hippocampus, a critical structure in learning and memory. When restraint was administered daily for two weeks, phosphorylated tau accumulated in the hippocampus, some of it in an insoluble form, which may represent an initial step in tangle formation.

To understand what factors were responsible for these changes, the investigators did similar experiments in mice engineered to lack either CRFR1 or CRFR2 in collaboration with Salk professors Kuo-Fen Lee and Wylie W. Vale in the Clayton Foundation Laboratories for Peptide Biology.

They found that mice lacking CRFR1 failed to show stress-induced tau modification, while in mice missing CRFR2, tau phosphorylation was increased.

This work indicates that crosstalk between CFR1 and CFR2 in some way modulates tau phosphorylation and suggests a biochemical mechanism for how chronic stress induces deleterious changes that may promote neurodegeneration and cognitive impairment characteristic of Alzheimer's disease.

Significantly, drugs that target CRF receptors are already in phase II clinical trials for depression and other mood disorders. This work indicates that these drugs could also potentially delay the progression of Alzheimer's disease.

InsideSalk 11|07 Issue | © Salk Institute for Biological Studies