It may someday be possible to diagnose and forecast risk for Alzheimer’s disease using skin cells, thanks to a small protein, or peptide, that few scientists previously associated with the disease.
School of Medicine researchers have discovered that skin cells from individuals with inherited forms of Alzheimer’s disease respond to the peptide bradykinin by triggering Alzheimer’s-like changes, whereas skin cells from healthy individuals do not. They found the same effect in skin cells from two young adults at high risk for developing the disease but who were too young to have clinical symptoms.
The study was recently published in The FASEB Journal and cited in the Internet-based Alzheimer’s Research Forum.
“No one has looked in-depth at the potential role of bradykinin in Alzheimer’s disease,” said principal investigator Nancy Baenziger, Ph.D., associate professor of anatomy and neurobiology. “Our findings need to be explored further in cases of noninherited Alzheimer’s disease, but this preliminary evidence is very encouraging.
“It’s possible that these results could eventually lead to a way of determining an individual’s risk of developing the disease before clinical symptoms arise, and that the bradykinin cascade could serve as a potential new drug target.”
Baenziger’s researchers previously identified several forms of bradykinin receptors that they termed H, I and L. They then developed probes that specifically detect the I and L forms.
The team used these probes to calculate the relative number of these receptors in samples from a National Institute on Aging database of skin cells from healthy individuals and those with genetic forms of the disease.
In one experiment, the cells were treated with a chemical that activates protein kinase C (PKC). The team found the number of I and L receptors increased by up to 450 percent in cells from Alzheimer’s patients, but there was almost no change in cells from healthy individuals.
The scientists then carried out more extensive studies of skin samples grouped according to the genetic defects that may have caused the disease. Skin cells from patients with the two most common forms of genetically linked Alzheimer’s disease — Presenilin-1 or Presenilin-2 — all had significantly increased numbers of I and L receptors compared with healthy individuals of the same age.
More strikingly, similar large increases in the number of I and L receptors were found in skin cells from a 19-year-old and a 20-year-old who both had Down syndrome. Individuals with Down syndrome frequently develop Alzheimer’s, typically around age 40.
“Our results suggest that changes in bradykinin receptors may be detectable decades before clinical symptoms of Alzheimer’s disease appear,” Baenziger said. “This is very exciting because early detection may ultimately prove to be key for preventing and treating the disease.”
The team also found that adding bradykinin itself to the skin cultures increased the number of I and L receptors by about 250 percent in cells from the two individuals with Down syndrome and from people with Presinilin-1 Alzheimer’s, but not in cells from healthy individuals. Similar increases were also observed in cells from a 77-year-old Alzheimer’s patient who had no presenilin mutations.
Both effects — those seen after stimulating PKC and after direct treatment with bradykinin — were blocked when cells first were treated with a chemical that inhibits PKC.
“This evidence suggests a pathway of events in which bradykinin activates PKC, which in turn triggers an increase in the number of these I and L receptors,” Baenziger said.
The team also identified another step in the molecular cascade and found evidence that this step is carried out by I and L receptors created during the earliest moments of the cascade.
One of the main characteristics of Alzheimer’s disease is thought to be the formation of tangled networks of a protein called tau in neurons.
Overactivity of a biochemical process known as phosphorylation is likely one of the first steps in the development of these tangles.
Baenziger’s team found that treatment with bradykinin increased the amount of tau phosphorylation by about 250 percent in skin cells from Alzheimer’s patients and from the Down syndrome patients, but not in cells from healthy individuals.
Moreover, the type of phosphorylation appeared similar to that seen in the brain during early Alzheimer’s disease.
Just as in the other experiments, treatment with a PKC inhibitor blocked the dramatic increase in tau phosphorylation.
“We have now shown that I and L bradykinin receptors are biochemically distinctive and target the tau protein that goes awry in Alzheimer’s disease,” Baenziger said.
“These clues are telling us something about the environment inside cells vulnerable to Alzheimer’s, which may eventually allow us to create molecular profiles that identify individuals vulnerable to developing this disease.”