Alzheimer's Pathology May Spread Along Synapses
February 10, 2012 — A new study supports the concept that Alzheimer's disease (AD) starts in the brain's memory center and spreads out from there to other parts of the brain.
The study team observed that in mice, tau pathology begins in the entorhinal cortex (EC) and then propagates along neuroanatomically linked pathways and from neuron to neuron across synapses.
The findings, reported online February 1 in PloS One, could have important implications on several fronts, researchers say.
"If, as our data suggest, tau pathology starts in the entorhinal cortex and emanates from there, the most effective approach may be to treat Alzheimer's the way we treat cancer — through early detection and treatment, before it has a chance to spread," Scott A. Small, MD, of the Taub Institute for Research on Alzheimer's Disease, Columbia University in New York City, who was involved in the research, noted in a statement.
"It is during this early stage that the disease will be most amenable to treatment. That is the exciting clinical promise down the road," Dr. Small added.
"Excitement" in the Research Community
Senior author Karen E. Duff, PhD, also from the Taub Institute, said, "If we can find the mechanism by which tau spreads from one cell to another, we could potentially stop it from jumping across the synapses — perhaps using some type of immunotherapy. This would prevent the disease from spreading to other regions of the brain, which is associated with more severe dementia."
Francis Collins, MD, PhD, director of the National Institutes of Health, mentioned the study earlier this week during a media briefing in which the Obama Administration announced increased funding for AD research.
He noted that "while this work was done in mice and has to be confirmed in humans, it has generated a lot of excitement among those working on treatments. It means that if we detect AD early, we might be able to stop the disease in its tracks by applying agents that can block its spread."
AD is characterized neuropathologically by the accumulation of plaques composed of amyloid-beta protein and neurofibrillary tangles composed of abnormal tau protein. The earliest stages of the disease show accumulation of abnormal tau in the EC, whereas later stages show accumulation in the hippocampus followed by neocortical areas.
"One of the most intriguing and poorly explored questions in the field," writes the study team, "is whether pathology and/or dysfunction of the EC initiates anatomical progression of the disease, or whether pathology and/or dysfunction in extrahippocampal areas develops independently, and is unrelated to events occurring in the EC."
There are a number of "interesting, albeit circumstantial observations that support the trans-synaptic spread hypothesis for AD both in terms of pathology development and functional outcome," they point out.
To investigate further, Dr. Duff and colleagues generated a transgenic mouse model expressing pathological human tau predominately in the entorhinal cortex. They then mapped the change in distribution of tau pathology as the mice aged.
They found that as the mice aged (from 10 to 11 months to older than 22 months old), the abnormal tau protein spread along a linked anatomical pathway from the EC to the hippocampus and neocortex, as is seen in early AD.
The researchers also found evidence suggesting that abnormal tau protein moved from neuron to neuron across synapses. "This means that neurons that are expressing tau are not only committing suicide, they are also committing homicide against their neighbors," Dr. Collins commented.
Feasible Target
Einar Sigurdsson, PhD, associate professor of physiology, neuroscience and psychiatry from New York University Langone Medical Center in New York City, who was not involved in the research, told Medscape Medical News the study "nicely confirms and extends prior studies by others that suggest extracellular tau is important for the spread of tau pathology throughout the brain."
"This mounting evidence for a key role of extracellular tau in the progression of the pathology has important implications for drug development," Dr. Sigurdsson said.
He noted, however, that the pharmaceutical industry has been "reluctant to develop therapies targeting tau aggregates because of the difficulty of getting drugs into cells. Now, this is considered a more feasible target for clearance by therapies such as antibodies, which my laboratory has been working on for over 10 years," Dr. Sigurdsson added.
The study was supported by the National Institutes of Neurological Disorders and Stroke and the National Institute on Aging. The authors, Dr. Collins, and Dr. Sigurdsson have disclosed no relevant financial relationships.
PloS One. Published online February 1, 2012.
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