For decades, researchers have debated whether Alzheimer's disease starts independently in vulnerable brain regions at differenttimes, or if it begins in one region and then spreads toneuroanatomically connected areas. A new study by ColumbiaUniversity Medical Center (CUMC) researchers strongly supports thelatter, demonstrating that abnormal tau protein, a key feature ofthe neurofibrillary tangles seen in the brains of those withAlzheimer's, propagates along linked brain circuits, "jumping" fromneuron to neuron. The findings, published in the online journal PloS One , open new opportunities for gaining a greater understanding ofAlzheimer's disease and other neurological diseases and fordeveloping therapies to halt its progression, according to seniorauthor Karen E. Duff, PhD, professor of pathology (in psychiatryand in the Taub Institute for Research on Alzheimer's Disease andthe Aging Brain) at CUMC and at the New York State PsychiatricInstitute. Alzheimer's disease, the most common form of dementia , is characterized by the accumulation of plaques (composed ofamyloid-beta protein) and fibrous tangles (composed of abnormaltau) in brain cells called neurons. |
Postmortem studies of humanbrains and neuroimaging studies have suggested that the disease,especially the neurofibrillary tangle pathology, begins in theentorhinal cortex, which plays a key role in memory. Then asAlzheimer's progresses, the disease appears in anatomically linkedhigher brain regions. "Earlier research, including functional MRI studies in humans, havealso supported this pattern of spread," said study coauthor ScottA. Small, MD, professor of neurology in the Sergievsky Center andin the Taub Institute for Research on Alzheimer's Disease and theAging Brain at CUMC. "But these various findings do notdefinitively show that Alzheimer's spreads directly from one brainregion to another." To look further into this issue, the CUMC researchers developed anovel transgenic mouse in which the gene for abnormal human tau isexpressed predominantly in the entorhinal cortex.
The brains of themice were analyzed at different time points over 22 months to mapthe spread of abnormal tau protein. The researchers found that as the mice aged, the abnormal human tauspread along a linked anatomical pathway, from the entorhinalcortex to the hippocampus to the neocortex. "This pattern very muchfollows the staging that we see at the earliest stages of humanAlzheimer's disease," said Dr. Duff.
The researchers also found evidence suggesting that the abnormaltau protein was moving from neuron to neuron across synapses, thejunctions that these cells use to communicate with each other. The findings of the study have important implications for therapy. "If, as our data suggest, tau pathology starts in the entorhinalcortex and emanates from there, the most effective approach may beto treat Alzheimer's the way we treat cancer - through early detection and treatment, before it has a chance tospread," said Dr. Small. "The best way to cure Alzheimer's may beto identify and treat it when it is just beginning, to haltprogression.
It is during this early stage that the disease will bemost amenable to treatment. That is the exciting clinical promisedown the road." Treatments could conceivably target tau during it extracellularphase, as it moves from cell to cell, added Dr. Duff. "If we canfind 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 thedisease from spreading to other regions of the brain, which isassociated with more severe dementia." Additional References Citations.
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