The first inkling of the unexpected link came when the investigators studied the behavior and brain anatomy of mice genetically engineered to produce human amyloid peptides in the brain. Amyloid peptides are sticky protein fragments that accumulate in the brains of patients with Alzheimer's disease. Production of amyloid peptides in genetically engineered mice causes deficits in learning and memory. The researchers were surprised to find that these deficits were tightly linked to biochemical changes in a group of brain cells that is relatively resistant to degeneration in Alzheimer's disease.
"Even though some neurons resist cell death in such neurodegenerative conditions, we found that they can still be drastically altered at the molecular level, and this probably has a major impact on their function," said lead author Jorge Palop, postdoctoral fellow in the laboratory of senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and professor of neurology and neuroscience at the University of California, San Francisco (UCSF).
The neurons the investigators studied, called granule cells, are located in a brain region (dentate gyrus) that plays an important role in the formation of memories. Normally, granule cells are full of a protein called calbindin that binds calcium and regulates its many functions in the cell. Mice that had lots of amyloid peptides in the brain and showed poor learning and memory in a maze test had very low levels of calbindin in their granule cells.
By examining genetically engineered mice with different degrees of deficits, the researchers were able to demonstrate a strong correlation between calbindin levels in granule cells and cognitive deficits in these experimental animal models. The lower the calbindin, the greater the cognitive deficits, suggesting that calbindin levels in granule cells might be useful as a diagnostic marker of Alzheimer-related cognitive deficits.
To further test this possibility, the investigators examined autopsy brain tissues from 15 patients with Alzheimer's disease and two from nondemented controls. Alzheimer's cases had major reductions in calbindin levels in their granule cells, with the worst depletions seen in the most severely demented cases.
"More cases will need to be analyzed to firmly establish how well calbindin reductions in granule cells correlate with specific cognitive deficits in the human condition," said Mucke. "The results we have obtained so far look very promising. Biochemical or radiological measures reflecting calbindin levels in granule cells might serve as useful surrogate markers of amyloid peptide-induced neuronal dysfunction. Such diagnostic markers are urgently needed to better assess promising new treatments for Alzheimer's disease."
Other authors on the study include Gladstone/UCSF researchers Brian Jones, Lisa Kekonius, Jeannie Chin, PhD, Gui-Qiu Yu, MS, and Jacob Raber, PhD, as well as Eliezer Masliah, MD, professor of pathology and neuroscience at the University of California at San Diego.
The Gladstone Institute of Neurological Disease is one of three research institutes of The J. David Gladstone Institutes, a private nonprofit biomedical research institution affiliated with UCSF. The institute is named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing interest in medical education and research.
The study was supported by the National Institute on Aging and the National Institute for Neurological Disorders and Stroke.