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Advances Reported In Targeting Pathology in Alzheimer Disease

ARTICLE IN BRIEF

The tau transgenic rat model — used in the research by Dr. Michal Novak — was generated by expressing a human truncated tau protein from sporadic cases of human Alzheimer disease (AD) in the brains of rats. Its neuronal expression led to the development of the neurofibrillary degeneration of AD. The truncated tau protein induced formation of Gallyas-positive intracellular and extracellular neurofibrillary tangles exhibiting Congo red birefringence and thioflavine S reactivity. The pathology is detectable in Western blotting as massive, misfolded tau complexes with the A68 triplet characteristic for AD. At the systemic levels, the human truncated tau protein induced oxidative stress and accumulation of free radicals; it stimulated inflammatory response, activation of microglial cells, and increased permeability of the blood-brain barrier. Finally, the neurofibrillary pathology caused by truncated tau resulted in neuronal dysfunction, progressive neurobehavioral impairment, and premature death of the animals.

At the International Conference on Alzheimer's Disease, two teams reported that tau levels were lowered in patients who received experimental anti-amyloid vaccines. Two other groups developing immunotherapies against tau aggregates have tested the vaccines in animal models and say that there is evidence that it reduces tangle burden and prevents cognitive decline.

The disease-modifying medicines in various stages of testing in patients with Alzheimer disease (AD) target the amyloid-filled plaque that accumulates outside of the neurons. Now, scientists are looking for ways to reduce the other hallmark pathology, the phosphorylated tau (phospho-tau) protein that builds up into the tangles found in the neurons. There is strong evidence that the tangles are further downstream of amyloid in the disease process and are more closely correlated with the cognitive signs that develop in the disease.

Tau's potential as a target for treatment was a central theme of this year's annual meeting of the International Conference on Alzheimer's Disease (ICAD), held in Hawaii.

Two teams reported that tau levels were lowered in patients who received experimental anti-amyloid vaccines. Two other groups developing immunotherapies against tau aggregates have tested the vaccines in animal models and say that there is evidence that it reduces tangle burden and prevents cognitive decline. AD scientists said that they are hopeful that such potential treatments could be in clinical trials in the next two years.

“It appears that targeting the early events — the deposition of amyloid-beta, [the peptide of 39–43 amino acids that appears to be the main constituent of amyloid plaques in the brains of AD patients] may influence later events (the phospho-tau deposition),” said Paul Aisen, MD, professor in the department of neurosciences at the University of California in San Diego and head of the Alzheimer's Disease Cooperative Study, who was not involved with the studies. “This is encouraging.”

“Until we have effective disease-modifying treatment, we should explore all plausible strategies,” said Dr. Aisen. “This definitely includes targeting tangles, and tau immunotherapy is an interesting approach. But just as all amyloid animal models have major limitations, we have no very good tau model.”

Still, he added, “there is animal evidence in support of both active and passive tau immunotherapy and I hope these programs continue to advance.”

ACTIVE IMMUNIZATION

While the relationship between amyloid plaques and tau tangles is still not clearly defined, the latest studies suggest the tau pathology occurs on the heels of the amyloid deposition and may be the driving force of neuronal cell damage and the symptoms of memory loss and dementia. That would explain why patients in the 2001 study by Elan Pharmaceuticals whose brains showed a reduced plaque burden did not have any improvements after the active immunization. The disease was already too far along.

“These patients still deteriorated,” said Delphine Boche, MD, of the University of Southampton in the United Kingdom, who was part of the team that measured amyloid beta [Abeta] and phospho-tau in the brains of the patients in the Elan active vaccine study. The trial was stopped in January 2002 after several patients developed meningoencephalitis linked to the treatment.

At the ICAD meeting, Dr. Boche reported on the results from autopsy samples from 10 AD patients who had received the active vaccine and in 28 AD patients who served as controls.

They looked at six regions of the brain hard hit in the disease — superior and middle temporal gyrus, medial frontal gyrus and inferior parietal lobule, entorhinal cortex, subiculum, and CA1 hippocampus — and found that 1.42 percent of the brain regions contained Abeta deposits in the immunized group versus 5.25 percent of the brain regions in the unvaccinated AD patients.

There was also a significant reduction in the phospho-tau load in the neuronal processes (0.72 in the vaccinated group compared to 1.08 percent in the controls) but they did not find any difference between the two groups in the level of phospho-tau in the neuronal cell bodies. The phospho-tau in the neuronal cell bodies is what contributes to the neurofibrillary tangles.

Dr. Boche said that the finding is important because it “links the two pathologies, Abeta and phospho-tau.” They are now measuring synaptic density and inflammation in the brains of these patients.

PASSIVE ABETA VACCINATION

Other scientists are studying the effects of passive Abeta vaccination on tau deposition. Kaj Blennow, MD, PhD, a professor and head of the clinical neurochemistry laboratory at the University of Gothenburg in Sweden, and his colleagues have been measuring biomarkers in the CSF of AD patients receiving the experimental monoclonal antibody, bapineuzumab.

Measurements of CSF in AD patients show decreases of Abeta levels and increases of phospho-tau. Dr. Blennow's group took CSF samples from two phase 2 bapineuzumab studies and found that there were decreases in total tau and phospho-tau, similar to what was reported in the Elan active immunotherapy trial. Total tau is a marker for neurodegeneration and phospho-tau is a marker for tangle formation.

Dr. Blennow said that the reduced tau levels in CSF are evidence that “the anti-Abeta treatment resulted in downstream effects on tangle formation. We are hoping that these anti-amyloid therapies will reduce the formation of tangles.”

ANIMAL MODELS TARGETING TAU

Scientists and pharmaceutical companies are now developing and testing treatments that target tau. “It may be better to target tau,” said Allai Boutajangout, PhD, a neuroscientist at New York University School (NYU) of Medicine. “If we are going to treat Alzheimer disease at a later stage in the disease process we need to go after a pathology like tau.”

The NYU lab is working on the development of passive immunotherapy targeted at the tau protein. They gave the vaccine to mice that are genetically bred to develop tau pathology. The scientists began giving the anti-tau antibody, which was donated by Peter Davies, PhD, head of the Litwin-Zucker Center for the Research on Alzheimer's Disease at the Feinstein Institute for Medical Research in Manhasset, NY, between two and three months. They continued to give it once a week for a total of 12 weeks.

They conducted behavioral tests when the mice were six months old and the animals that received the vaccine performed better on a balance beam than the animals that had no exposure to the vaccine. When the scientists studied brain sections, they found a 58 percent reduction in tau pathology in the vaccinated group. The animals that had high antibody levels had low tau aggregation.

“Future studies will determine the feasibility of this approach with other monoclonals and in different tangle models that more closely resemble Alzheimer disease,” said Dr. Boutajangout.

Animal models of the tau pathology will hopefully help scientists understand how the soluable tau protein misfolds into an insoluble form that clumps into tangles. Michal Novak, PhD, of the Institute of Neuroimmunology in Slovakia, studied a rat model of tauopathy to figure out the phosphorylated patterns of tau proteins as they transition from a disordered form to a misfolded one. The hope was to identify tau species that could be used to develop an effective vaccine.

Dr. Novak and his colleagues performed western blot analysis of soluble and insoluble tau proteins isolated from the rats at various stages during the pathological illness. They identified a phospho-tau species that was directly involved in the conversion between the soluble and insoluble forms. The species created a template that was used by the soluble forms to become insoluble. They used the tau form to make a vaccine and immunized the animals. They were able to delay the neurobehavioral impairment and blocked the development of the key stages when the protein becomes misfolded. This resulted in less phospho-tau and reduced numbers of misfolded tau protein in the brain.

If such strategies work for AD, scientists say that the treatment could be useful for other tauopathies such as frontotemporal dementia and progressive supranuclear palsy.