Today's Sarasota paper
A discovery that could prove capable of dissolving a major impasse in Alzheimer’s disease research has been published by a team of scientists at Sarasota’s Roskamp Institute.
The prevalence of Alzheimer’s is expected to triple in the next 35 years, with the aging of the baby boom generation, and treatment costs will soar. The frustrating search for a drug that can cure — or at least prevent — this devastating and fatal memory disorder ran up against the reality that its origins are more complex than scientists first thought, and involve at least three ways the human body can fail the brain.
But Roskamp researchers say they have isolated just one mechanism that affects them all.
“We have shown that by disrupting a single enzyme, we can actually control those three different processes,” said Daniel Paris, a senior scientist at Roskamp and lead author of the paper published online in the Journal of Biological Chemistry.
This early result in the lab, if borne out in human trials, could lead to something researchers have started to think is too good to be true: a simple drug that could target one cellular on-off switch that connects to all the interlocking symptoms of Alzheimer’s.
The quest began 10 years ago, with an under-the-radar blood pressure drug that Roskamp scientists proved could reduce the beta amyloid buildup — or plaque — that is found in the brains of Alzheimer’s patients. When the scientific community began to suspect that beta amyloid was not the sole culprit involved in Alzheimer’s, excitement faded about this and other drugs in the pipeline.
But then Roskamp researchers found that its blood-pressure drug — nilvadipine, a calcium-channel blocker — also worked to suppress another component of Alzheimer’s: inflammation. They decided to test it on the third known complication — tau “tangles” that proliferate in the brain — and found it worked to reduce those as well.
The question, said Paris, was why.
“We were starting to scratch our heads trying to figure out how a drug can do so many things,” he said. “We tried to dissect all the molecular events that were affected by the drug.”
About 18 months ago, after an exhaustive scrutiny of an uncountable number of proteins that nilvadipine might affect on its pathway through the human body, the team found their enzyme — a single key that could turn in three locks.
“We kind of drew a map of all the events that are connecting the amyloid pathology, the abnormality of the tau protein and the inflammation,” Paris said. “All those events intersected to a particular target that we call syk — spleen tyrosine kinase.”
Syk — named after the spleen because that’s where biologists first identified it — is also suspected of playing a role in other inflammatory disorders, like rheumatoid arthritis and lupus. That means there are additional drugs in the pipeline that target syk — and may do an even better job than the variant of nilvadipine that the Roskamp team developed.
A starting point
The team — in addition to Paris, they are Sarasotans Ghania Ait-Ghezala, Corbin Bachmeier, Gary Laco, David Beaulieu-Abdelahad, Yong Lin, Chao Jin, and institute directors Fiona Crawford and Michael Mullan — tested some of the other syk suppressors now available, and validated their effectiveness at the cellular level.
They submitted their findings to the peer-reviewed journal at the end of August, Crawford said, and the editors accepted the paper quickly, calling it comprehensive and significant.
“The critique came back and they basically said you forgot to put a period at the end of this line and a comma here,” she said. “No negative comments at all.”
Neurologist R. Scott Turner, director of the Memory Disorders Program at Georgetown University, said this week he found the paper interesting.
“These findings, however, are all preclinical — with promising data utilizing cell cultures and animal models of Alzheimer’s disease,” he said. “With additional evidence of safety and suggestions of potential efficacy, however, these findings add support for translational research with this drug — with human studies.”
After so many disheartening dead ends, researchers in this field tend to be cautious. Paris said it is “too soon to tell” if the emergence of this new idea will amount to the breakthrough pharmaceutical companies have been seeking.
“For us, it’s given us a new starting point,” he said: “a simple idea to test to see if we’re on the right track.”
But Crawford said that after years of having so little to offer Alzheimer’s patients and their caregivers, she is comfortable showing a bit of excitement about syk.
“This is nice,” she said. “You only have to get one drug approved and it’s doing all three things and we already know that one drug that does this is safe and well-targeted. This is a positive message about something that is going to have real relevance for them in the next few years.”
About Roskamp Institute
History: Robert Roskamp, a philanthropist and Sarasota-based developer of senior living facilities, founded the nonprofit institute with his wife, Diane, in 2003. The basis for its current work was set more than a decade ago by co-directors Michael Mullan and Fiona Crawford, members of a team of scientists who discovered in the early 1990s that the onset of Alzheimer’s disease was directly related to the accumulation of a protein called beta amyloid.
Mission: The institute is dedicated to understanding the causes of, and finding novel therapies for, neuropsychiatric and neurodegenerative disorders, with an emphasis on Alzheimer’s. Its clinic focuses on clinical trials, and also diagnosis and treatment.
Evolution: The institute has long experimented with funding its research through for-profit partnerships. One is Sci-Brain, a lifestyle modification venture launched in 2013, using a “Brain Reserve Index” that takes into account fitness, diet and medical history. This year a Virginia drug company, Star Scientific — in which Roskamp was a major stakeholder and whose CEO was involved in a political scandal related to claims for its tobacco-derived supplement Anatabloc — was renamed Rock Creek Pharmaceuticals and moved to the institute.
Nilvadipine: For 10 years the institute has investigated this blood pressure drug, more widely used in Ireland, for its potential as an Alzheimer’s therapy. A clinical trial in humans has been underway in Europe since 2011. The institute’s latest discovery is that nilvadipine’s effectiveness against an single enzyme, syk — and not its ability to lower blood pressure — could explain its impact on the biomarkers for Alzheimer’s.
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BARBARA PETERS SMITH
Barbara Peters Smith covers aging issues for the Sarasota Herald Tribune. She can be reached byemail or call (941) 361-4936.
Last modified: October 28, 2014
