Scientists have long debated whether Alzheimer’s disease starts in separate regions of the brain independently and at different times, or if it begins in one region and then spreads. Data from researchers at Columbia University Medical Center supports the latter model, showing that abnormal tau protein — a key feature observed in the brains of patients with Alzheimer’s disease — propagates along anatomically connected networks, between connected and vulnerable neurons. The study was published earlier this month in the online journal PLoS ONE .
A hallmark of Alzheimer’s Disease is the accumulation of ‘neurofibrillary tangles,’ aggregated clumps of a mutated form of microtubule associated protein tau (MAPT).
In the earliest stages of Alzheimer’s Disease, these tangles accumulate primarily in the entorhinal cortex (EC), a region of the brain involved in memory formation and consolidation. As the disease progresses, these tau aggregates can be seen in the hippocampus and other areas of the brain. But it is not clear whether the pathology that starts in the entorhinal cortex travels to these other brain regions, or if it arises there independently.
To date, mouse models of Alzheimer’s have been made that have high levels of tau aggregates all over the brain. These have provided valuable insights into the disease, but could not be used to analyze its molecular progression over time or space. Scientists in Karen Duff’s lab at the Taub Institute for Alzheimer’s Disease Research, Columbia University, New York, just made new mice that express the pathological version of human tau protein only in the entorhinal cortex. They then compared the distribution of tau aggregates in young mice and old mice.
As the mice aged, the scientists found that the tau aggregates spread from the entorhinal cortex to regions that are connected to it through one or more synapses, like the hippocampus and neocortex. The hippocampus is important in cementing short term memories into long term memories and is also involved in spatial navigation, and the neocortex plays a role in higher level cognitive functions like conscious thought and language. Although the mechanism by which these tau aggregates affect neurodegeneration is not quite known, their accumulation has definitely been correlated with more severe pathology and ultimately neuronal cell death.
This new mouse model shows that Alzheimer’s Disease progresses through what the authors call an “anatomical cascade,” rather than developing multiple times in independent events spread throughout the brain. The earliest stages of the disease, when the tau tangles are restricted to the entorhinal cortex and connected areas, are not associated with any mental decline. The authors thus hope that the location of these ‘neurofibrillary tangles’ can now be used as a temporal biomarker, and that strategies might soon be developed to halt their spread.
- Liu et al. Trans-Synaptic Spread of Tau Pathology In Vivo. PLoS One. 2012;7(2):e31302. Epub 2012 Feb 1.