Researchers around the world have devoted themselves to devising ways of blocking the production or accumulation of beta-amyloid, the protein that accumulates as plaques in the brains of persons with Alzheimer disease. Now scientists are studying other protein targets, including tau, which accumulates in Alzheimer brains and disrupts the activity of brain networks, and the regulator protein CD33.
Last month, Dan Skovronsky, MD, PhD, Eli Lilly & Company vice president of tailored therapeutics, announced that the drug company was pursuing several potential treatments targeting the neurofibrillary tangles caused by tau and had just bought the rights to 2 tests for measuring tangles in the brain.
“The whole field has been amyloid-centric, amyloid-driven, but we need more than that. That’s why we’re investing in tau,” Dr Skovronsky told The Wall Street Journal. “The most meaningful impact in Alzheimer’s might involve targeting multiple pathways and using combinations of drugs.”
Targeting a reduction in levels of the tau protein is likely to be a useful therapeutic approach in Alzheimer disease in parallel with efforts to target beta-amyloid levels, according to research that has identified a new set of genetic markers for the disease.
“We identified several genes that modulate tau levels in the cerebrospinal fluid. These genes may be useful therapeutic targets for Alzheimer disease,” senior investigator Alison M. Goate, DPhil, Professor of Genetics in Psychiatry at Washington University School of Medicine in St Louis, told ConsultantLive.
Higher levels of tau and a phosphorylated version of tau (p-tau) in the cerebrospinal fluid are thought to reflect both tangle formation and neuronal cell death. Because tau levels are proportional to the cell death, higher tau levels are associated with more severe dementia, Dr Goate noted.
In the April 24 online edition of Neuron, Dr Goate and colleagues reported that they had identified several genes that are associated with tau levels, and “thus targeting these pathways may provide a more specific means of reducing tau or p-tau levels,” she said.
If drugs could be developed to target tau, they might prevent much of the neurodegeneration that characterizes Alzheimer disease and, in that way, help prevent or delay dementia, Dr Goate suggested.
Blocking CD33 Activity
Another potential strategy for developing treatments to stem the disease process is based on unclogging removal of toxic debris that accumulates in patients’ brains by blocking activity of CD33.
“Too much CD33 appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” said Rudolph Tanzi, PhD, of Massachusetts General Hospital and Harvard University, in an NIH statement. “Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”
Dr Tanzi and colleagues have found overexpression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer disease. What’s more, they found reduced amounts of CD33 on the surface of microglia and less beta-amyloid in the brains of persons who inherited a version of the CD33 gene that protected them from Alzheimer disease.
There also is evidence to suggest that CD33 works along with another Alzheimer risk gene in microglia to regulate inflammation in the brain.
Early detection of Alzheimer disease is critical to give persons at risk a better chance of receiving effective treatment. Perhaps studies of proteins other than beta-amyloid will lead to useful therapeutic targets.