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VA Research: Alzheimer’s Disease

 

 

 

Having established that the introduction of soluble factors can help restore function and plasticity to an aging brain, Wyss-Coray and his team are hunting for the specific factors involved in this rejuvenation. The team has already identified and reported on one cytokine – colony stimulating factor 2, or CSF2 – that appears to be involved in mediating some of these effects.

Because there is still so much to learn about the etiology of Alzheimer’s disease, the bulk of VA’s research concerns basic biomedical science.

The team is currently conducting a clinical trial aimed both at creating some of these rejuvenating effects in Alzheimer’s patients and in gaining a better understanding of the soluble cytokines involved in the disease: Once a week, participants with mild to moderate Alzheimer’s are given an infusion of plasma from donors between the ages of 20 and 30; after a month, they’re given functional evaluations. “The study has 18 subjects and it’s still ongoing,” said Wyss-Coray. “And we hope to have it completed by the end of the year.”

Another investigator of Alzheimer’s at the molecular level is Chad Dickey, Ph.D., an associate professor of molecular medicine at the Byrd Alzheimer’s Institute at the University of South Florida and a research scientist at the James A. Haley VAMC in Tampa, Florida. Dickey studies the workings of a class of proteins known as “chaperones,” which ensure the correct assembly or disassembly of intracellular structures – the folding and unfolding of other proteins – in the brain.

“If [a protein] is not folded properly, chaperones can either degrade it or they can try to refold it,” explained Dickey. “We think that’s a really critical point for a lot of problems inside neurons, because these chaperones aren’t doing their job quite right.” Sometimes a chaperone can get stuck, trying to fold a malformed protein that should simply be discarded – and this can lead to the accumulation of tau proteins within the cell, which interferes with healthy protein signaling. “[Tau accumulation] is basically clogging up this really important system, and that triggers a sort of toxic pathway,” Dickey said. “We think of it as a toxic pathway that eventually leads to neuronal loss and to some of the cell damage that occurs inside the Alzheimer’s brain.”

Alzheimer's disease research

Drs. Sam Gandy and Greg Elder (at microscope), with the Bronx VA Medical Center, are studying a neuron-generating compound that shows promise for both Alzheimer’s disease and traumatic brain injury.

In his laboratory, Dickey and his team are looking for compounds that can inhibit these toxic pathways and steer chaperones back on track in the neurons of mice that model Alzheimer’s. “I think the chaperone field has lagged behind as far as drug development goes,” he said. “We’re trying to find better targets in the chaperone family that would be specific for tau.”

Susan Farr, Ph.D., a research physiologist at the St. Louis VAMC and professor of medicine at Saint Louis University, is investigating other ways of inhibiting Alzheimer’s-related brain abnormalities using mouse models of aging or Alzheimer’s. Farr’s work focuses on countering the synthesis and accumulation of disease-associated proteins with “antisense” compounds, or chains of nucleotides engineered to bind with a segment of messenger RNA (mRNA) and effectively deactivate a faulty gene signal – the instruction, for example, to create more beta-amyloid protein. In the spring of last year, her team reported the development of an antisense compound that reversed Alzheimer’s symptoms in mice.

The antisense used by Farr’s team, oligonucleotide-1 (OL-1), works by inhibiting the amyloid precursor proteins (APPs) concentrated in the synapses of neurons. “The antisense gets in to the central nervous system and binds to APP,” she explained, “blocking the cleavage of APP and thereby decreasing the production of beta-amyloid. So we’ve gone through a whole process of creating multiple antisenses, and identifying the sequences of oligonucleotides that produce the best effect on learning and memory.”

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Craig Collins is a veteran freelance writer and a regular Faircount Media Group contributor who...