BDNF, a Brain Substance, Could be Useful in Treating Alzheimer’s Disease

BDNF, a brain substance, could be useful in treating Alzheimer’s disease. It worked in test animals whose brains were impaired by a condition similar to Alzheimer's. The findings of US scientists have been published in the journal Nature Medicine.
“We saw a potent effect,” said Dr. Mark Tuszynski, a neurologist and neuroscientist at the University of California San Diego who co-authored the paper with 16 other colleagues.

Treated with extra amounts of a protein called brain-derived neurotrophic factor, or BDNF – found naturally in the brains of mammals, including humans – all of the test animals displayed neural or cognitive improvement. Brain cells that should have died did not. Atrophied cells recovered. Functions such as learning and memory were preserved or improved.

If the test animals' health remains good for another year or so, Tuszynski said, the next step would be to conduct Phase 1 safety trials for humans.

“Seeing these effects, especially in the monkeys, is very encouraging,” he said. “BDNF is a direct intervention. It has the potential to significantly boost brain function and prevent cell death (in Alzheimer's patients).”

The protein brain-derived neurotrophic factor (BDNF) has been the focus of intense interest in the Alzheimer's field for a number of years. BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex. This discovery kindled hope in the early 1990s that Alzheimer's could be slowed or halted if brain levels of BDNF could be increased. The idea gained support with the observation that BDNF gene activity and protein levels are reduced in AD brains.

Researchers hope BDNF changes that. The protein is normally produced throughout life in the entorhinal cortex, an important memory center in the brain. This is where the effects of Alzheimer's typically appear first, contributing to the disease's cardinal symptom of short-term memory loss.Alzheimer's patients have diminished levels of BDNF.

In their study, Tuszynski and colleagues injected BDNF or a harmless virus carrying the BDNF gene into the entorhinal cortices of test animals. The technique is similar to one used by Tuszynski in an ongoing study in which human nerve growth factor (NGF) is injected into humans who have been diagnosed with Alzheimer's.

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The NGF study, which is entering Phase 2 multicenter trials across the country, has produced positive, if not spectacular, results. Patients and doctors report improvement – or at least a perceived slower rate of memory loss – but NGF is not considered to be a cure, writes Scott LaFee in San Diego Tribune.

“Our objective with NGF is to boost neuron function, to significantly and meaningfully delay Alzheimer's in a way that improves a patient's quality of life,” Tuszynski said. “But NGF is not a direct intervention. Ultimately, neurons affected by Alzheimer's will decay and die from the disease.”

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BDNF would appear to possess greater possibilities. The protein directly affects brain cells in two beneficial ways. First, it turns off the internal machinery that can order cells to commit suicide in a process called programmed cell death, or apoptosis. Second, it promotes the expression of genes that are “the hallmark of a healthy cell,” said Tuszynski.

Compared with control groups not receiving BDNF, treated animals in the study demonstrated significant improvement in a variety of learning and memory tests. Their brains showed restored BDNF gene expression, greater cell size, improved cell communications and revived functioning of neurons that, in untreated animals, degenerated.

The benefits extended beyond the entorhinal cortex to the hippocampus, a critical brain region where short-term memory is processed.

But BDNF is not easy to work with. It is a large molecule and cannot pass the blood-brain barrier, which means the protein or BDNF-producing genes must be injected directly into the brain. And, as with a powerful fertilizer, too much of it can be counterproductive.

“You have to be careful in efforts to turn on gene expression of things like BDNF,” said Tuszynski. “When you make extra amounts, if it broadly circulates in the brain, it tends to cause adverse side effects, like sensory disturbances, pain, weight loss, nausea. One of our challenges is to effectively turn on the gene where it's needed, but not where it's not.”

The findings encourage Tuszynski, who also works for the Veteran Affairs Medical Center in San Diego, for another reason: The protein is effective even though it appears to have no effect on amyloid plaques.

Amyloid plaques are deposits of amyloid proteins and other matter that are a primary indicator of Alzheimer's disease. Numerous research efforts are under way to study and remedy amyloid plaques, Tuszynski said. The fact that BDNF appears not to be associated with amyloid plaques suggests it might provide a second, independent therapy, one that could ultimately be combined with successful amyloid treatments to produce even more beneficial results.

“It sounds like they have found a novel approach,” one that might multiply the chances of eventual therapeutic success, said Kenneth Kosik, co-director of UC Santa Barbara's Neuroscience Research Institute, who is investigating the role of another brain protein called BAG2.

Other scientists expressed similar optimism. “It seems to me very promising,” said Dr. Fernando Gomez-Pinilla, a professor of neurosurgery at UCLA who has studied how exercise and foods rich in omega-3 fatty acids elevate natural BDNF levels.

“Among all of the molecules associated with common dementia, BDNF is maybe the most important,” said Gomez-Pinilla. “It plays many roles. We know how it works. It presents many, many possibilities.”

Existing therapeutic options for Alzheimer's are severely limited; the drugs currently used do not reverse or prevent the disease. They only manage symptoms.

“We are desperately looking for new approaches and new interventions,” said Dr. Douglas Galasko, director of the Shiley-Marcos Alzheimer's Disease Research Center at UCSD.

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