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Paul E. Sawchenko

 

Paul E. Sawchenko

Paul E. Sawchenko

Professor and Laboratory Head
Laboratory of Neuronal Structure and Function

"Our ability to respond to stress is a double-edged sword. In the short term, stress responses facilitate our ability to cope with real or perceived threats to our well being. If stress exposure is repeated or sustained, however, these responses can precipitate or worsen any number of pathological states, including neurodegenerative diseases."

While aging is far and away the greatest risk factor for developing Alzheimer's disease, individuals who are most prone to experience stress are more than twice as likely to develop Alzheimer's disease. The nature of the link between the two, however, has been elusive.

In Alzheimer's disease, amyloid plaques accumulate outside brain cells, and neurofibrillary tangles, consisting of a modified form of a protein called tau, litter the inside of neurons. Tau, in its unmodified form, helps stabilize an intracellular network of microtubules that is essential for maintaining the normal form and function of brain cells. In Alzheimer's disease, phosphate groups attach to tau; tau then loses its grip on the microtubules and starts to collapse into insoluble protein fibers, which ultimately cause cell death.

Previous studies have shown that extreme stress can induce tau phosphorylation. Sawchenko and his group sought to determine whether exposure to milder stress, of the kind we experience in our daily lives, can also induce tau phosphorylation. Physically restraining mice for half an hour, a situation that mimics the body's reaction to low-level anxiety, fear, or social stress, resulted only in a transient phosphorylation of tau. When chronic stress was simulated by repeating the procedure every day for two weeks, however, the modification lasted long enough to let tau molecules tumble off the cytoskeleton and accumulate in insoluble heaps of protein. In pursuing the mechanisms underlying these effects, Sawchenko found that the potentially brain-damaging effects of emotional stress are relayed through the two known corticotropin-releasing factor receptors, CRFR1 and CRFR2, which are part of a central switchboard that mediates a number of the body's responses to stress. Using mice genetically engineered to lack either CRFR1 or CRFR2 revealed that the absence of CRFR1 blocked stress-induced tau phosphorylation, while in mice missing CRFR2 the effect was amplified.

Pharmaceutical companies are actively developing small molecule drugs that bind CRF receptors for treating depression and other mood disorders. Sawchenko's work may have uncovered another application: delaying or preventing the progression of Alzheimer's disease.

Lab Photo

Left to right:
Robert Rissman, Carlos Arias, Charles Peto, Jason Radley, Linda Feighery, Paul E. Sawchenko, Kris Trulock, Borja Garcia Bueno, Jordi Serrats, Aditya Rayasam

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Paul E. Sawchenko

Faculty

Paul E. Sawchenko

Paul E. Sawchenko

Professor and Laboratory Head
Laboratory of Neuronal Structure and Function

Paul E. Sawchenko, professor and head of the Laboratory of Neuronal Structure and Function, studies how the brain is organized to control such bodily functions as eating, drinking, blood pressure and response to stress.

Sawchenko's work attempts to understand the complex networks of brain cells that are involved in each of these essential functions, to identify specific molecules that affect communication between cells that make up these networks, and how these molecules are regulated under stressful conditions. These studies could have implications for the understanding and management of pathological conditions including hypertension, autoimmune diseases and stress-related psychiatric disorders, such as certain forms of depression and anorexia nervosa.

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