Interestingly, Uch-L1--a protein found almost exclusively in nerve cells--was also found at reduced levels in the Alzheimer's brain. Unpublished studies by Shelanski's group found that cells treated with Aß exhibited a rapid drop in Uch-L1, he said.
To further investigate in the current study, the researchers treated brain slices with a chemical that blocks Uch-L1 function. The treated brain tissue displayed a decline in "long-term potentiation" (LTP), a process whereby nerve connections are strengthened. LTP is regarded as the cellular basis for learning and memory.
Treatments that restored Uch-L1 levels corrected deficits in nerve transmission both in brain slices treated with Aß and in slices taken from transgenic mice with mutations that lead to elevated Aß and associated cognitive decline.
The researchers next asked whether Uch-L1 played an important role in fear conditioning, a form of learning known to be impaired in several mouse models of Alzheimer's disease.
For fear conditioning, mice treated with the Uch-L1 inhibitor and control mice were placed in a novel context (a fear-conditioning box) and exposed to a tone paired with a mild foot shock. Their ability to learn fear was tested 24 hr later by measuring "freezing" behavior in response to the box or the auditory cue. Contextual versus cued responses represent different forms of learning that depend on different parts of the brain.
A day after their exposure to the shock, mice with reduced levels of Uch-L1 showed a decrease in freezing behavior to 65% that of normal mice when placed in the box. The differences between treated and untreated mice persisted 7, 14, and 21 days after exposure to the electric shock, they reported.
On the other hand, the mice showed no differences in response to the auditory