– USF collaborates on study targeting immune response of amyloid plaques –

May 30, 2008 — Interrupting a signaling pathway in certain immune system cells in mice had the opposite effect researchers expected but opened the possibility of a new approach to treating Alzheimer’s disease, according to an article appearing online May 30 in the journal Nature Medicine.

University of South Florida neuroscientist Jun Tan, MD, PhD, was a collaborator on the study, and colleague Terrence Town, PhD, a graduate of USF’s Neuroscience Concentration PhD Program who is now at Cedars-Sinai Medical Center, was the study’s lead author.

The intervention targeted the sticky plaque buildup in the brains of patients with Alzheimer’s disease, using immune system cells (macrophages) from outside the brain. In the animal study, these cells were attracted to the plaque and able to cross the blood-brain barrier, a natural barrier that prevents most substances from entering the brain from the bloodstream. Plaque deposits were significantly reduced and mice performed better on behavioral tests.

“Attempts to develop therapies for Alzheimer’s disease have been difficult because most rely on getting a therapeutic molecule or antibody across the blood-brain barrier,” said Dr. Town, a research scientist in the Departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai and Maxine Dunitz Neurosurgical Institute, the hospital’s neurosurgical research center. “If results from our study in mice engineered to develop Alzheimer’s-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques.”

Amyloid plaques, composed of a protein called amyloid-b peptide (Ab), are thought to damage brain nerve cells (neurons) and stimulate a response in nearby inflammatory cells called microglia. Theoretically, Alzheimer’s might be treated by somehow preventing or removing the plaque buildup and calming the inflammation.

Dr. Town’s group and others, including Dr. Jun’s team at USF, have worked at the interface of the immune system and the brain. Their research suggests that the kind of chronic, low-level inflammatory response seen in Alzheimer’s disease is damaging, and they are looking a way to turn this response into a therapy to combat Alzheimer’s.

Attempts to stimulate a beneficial immune response have been limited not only by access – the blood-brain barrier – but also by the fact that the brain is an “immune privileged” environment, not conducive to a strong immune response from microglia and other brain-resident immune cells.

Earlier studies demonstrated that an immunosuppressive molecule called transforming growth factor-b (TGF-b) is upregulated in the brains of patients with Alzheimer’s disease. This upregulation may represent the brain’s attempt to return to normalcy by quieting the immune response around the amyloid plaques. Dr. Town and his colleagues used genetically-engineered mice to study the effects in the brain of blocking the TGF-b molecule on immune cells outside the brain (peripheral macrophages).

“If these experimental animals are representative of the clinical syndrome of Alzheimer’s disease, we may have a therapeutic target that we did not have before – TGF-b on these peripheral macrophages,” said study co-author Dr. Tan, professor and Robert A. Silver chair in Developmental Neurobiology at USF.

“We’re now investigating the molecular mechanisms that allow the cells to cross the blood-brain barrier, but it appears that by blocking TGF-b, we’re able to lower their threshold for activation and empower them to enter the brain where they’re homing to the amyloid plaques.”

Originally, the researchers thought that blocking the TGF-b response in peripheral macrophages would worsen Alzheimer’s-like pathology because it would cause those cells to become hyperstimulated or hyperactivated. They would then enter the brain and likely exacerbate the brain inflammatory and immune response brought on by the amyloid plaques.

“What we found was the exact opposite – which gave us the opportunity to learn something new about the biology of Alzheimer’s disease,” Dr. Town said. “When we behaviorally tested the mice, we found they were doing better by some measures. And when we looked at the brains of these mice, we noticed that the amyloid plaques were strikingly reduced – as much as 90 percent by some methods.”

Further studies confirmed that macrophages from the blood were coming into the brain and – like PAC-MAN – devouring the plaque.

In addition to Cedars-Sinai and USF, researchers from Yale University, Saitama University in Japan, Johns Hopkins University, and the University of Michigan were involved in the study. The work was supported by an Alzheimer’s Association Grant and a National Institutes of Health grant.

Dr. Town graduated from USF Health in 2002 with an Outstanding Student Award and completed his postdoctoral training at Yale Medical School. He has continued highly productive collaborations with Dr. Tan – the two authoring nearly 35 peer-reviewed papers together.

“Dr Town was our first PhD student when we started our Neuroscience program,” said Paul R. Sanberg, PhD, DSc, director of the USF Center for Aging and Brain Repair. “It’s a great priviledge to see him making such important discoveries and continuing research with Dr Tan and other USF scientists.”

– Story adapted from a news release by Cedars-Sinai Medical Center