By Emily Leclerc | Waisman Science Writer
At a Glance
- Loss of synapses, the connections between neurons that allow them to communicate, is a primary driver of cognitive decline in Alzheimer’s disease.
- Researchers expected a strong connection between synapse loss and tau buildup but the relationship was more nuanced than expected. Researchers found weak connections between tau buildup and synapse loss in the parts of the brain where tau typically first appears.
- Looking at the brain as a whole revealed a stronger connection between tau and synapse loss. The brain’s compensatory mechanisms might be obscuring tau’s effect on synapses.
The connection between a key Alzheimer’s-related protein and the loss of brain cell communication may be more nuanced and complex than previously believed – an insight that could inform how scientists approach developing treatments for the disease. A new study from the lab of Waisman investigator Brad Christian, PhD, professor of medical physics and psychiatry, along with collaborators Barbara Bendlin, PhD, Waisman affiliate and professor of medicine and Sterling Johnson, PhD, Waisman affiliate and professor of medicine, found that the connection between the buildup of tau in the brain in Alzheimer’s and the decreases in neuronal communication that is a primary driver of cognitive decline in the condition is not as straightforward as anticipated.
Alzheimer’s Disease, a neurodegenerative condition and the most common cause of dementia, is biologically defined by the buildup of two different proteins in the brain – amyloid β (beta) and neurofibrillary tau. “Tau tangles are a signature feature of what we see with Alzheimer’s disease. The amyloid plaques tend to buildup much earlier and haven’t been shown to affect cognitive function,” Christian says. “The tau tangles come later and their presence does correlate with declined cognitive function. So, they are very important to study.” But tau’s relationship to the loss of synapses, which is one of the primary drivers of cognitive decline in Alzheimer’s, is not well understood.
Synapses are the connections between neurons that allow them to communicate back and forth. In Alzheimer’s, as the disease progresses, the number of synapses throughout the brain decreases significantly as the neurons are damaged by the buildup of amyloid β and tau. This decrease in synaptic density is one of the main reasons for the symptoms of dementia that individuals experience. “The big question for this research and the new paper is do we see this relationship where elevated levels of tau are associated with reduced synaptic density?” says Alexandra DiFilippo, PhD, former member of Christian’s lab and first author on the new paper.
DiFilippo’s paper, “Examining the Association Between Synaptic Density and Neurofibrillary Tau Among Cognitively Impaired and Unimpaired Older Adults with and without Alzheimer’s Disease Pathology,” was published in the journal Alzheimer’s and Dementia.
Using positron emission tomography (PET) imaging, they looked at two areas of the brain specifically while also collecting data on the brain as a whole. Tau tangles typically first start appearing in the regions of the hippocampus, the brain region responsible for memory and learning, and the entorhinal cortex, a brain region connected to the hippocampus that is involved in memory, navigation, and the perception of time. “Our group of study participants were primarily in the early stages of Alzheimer’s Disease so we thought that if we are going to see something, it would likely be in those two brain regions,” DiFilippo says.
Contrary to what they had originally hypothesized, Christian and DiFilippo found almost no relationship between tau tangles and the synaptic density of the hippocampus and entorhinal cortex. Even in comparisons between participants with Alzheimer’s who had cognitive decline and those with Alzheimer’s who did not have cognitive decline, the group found a very weak relationship. They were surprised that there wasn’t a stronger relationship considering tau tangles’ well-established neurotoxic affects. “We expected a stronger connection,” DiFilippo says.
When DiFilippo looked at the brain as a whole though, she started to see more of a relationship between tau and decreasing synaptic density. “When we looked at some of the regions outside of the hippocampus and entorhinal cortex, we started to see a bit more of a relationship,” DiFilippo says. “Maybe this means that it’s difficult to interpret tau’s effects locally, such as inside of the hippocampus, and we need to have a more global approach in the future.”
These results suggest to Christian and DiFilippo that the relationship between tau and synaptic density is not as straight forward as they originally anticipated. There is likely complex interplay between the tau tangles, synaptic density, and different compensatory processes. The brain has several tactics for trying to heal itself and that can cloud the full extent of a relationship like this one.
This paper is an important starting point for understanding the impact of tau tangles on synaptic density in Alzheimer’s disease. It leaves a lot of potential research paths to follow including how tau impacts synapses throughout the brain, how that relationship is complicated by the brain trying to heal itself, and the use of magnetic resonance imaging (MRI) and other measures to look at tau tangles from different angles.
“We also want to start to translate this information into studies with our ABC-DS group,” Christian says. ABC-DS or the Alzheimer’s Biomarkers Consortium – Down Syndrome is a large multi-site research initiative to find biomarkers to track Alzheimer’s disease in Down syndrome. “Individuals with Down syndrome experience a very accelerated disease progression. Tau accumulates earlier and faster. We want to see if the drop in the synaptic density comes on faster as well,” Christian adds.
Understanding this relationship has the potential to provide new ways to design treatments and therapies for Alzheimer’s but unraveling the complex systems at play takes time and dedicated researchers. “This is a first step,” DiFilippo says, “toward looking at synapse density and these kinds of neurodegeneration markers.”
This research was funded by the National Institute on Aging, where data acquisition and sharing were accomplished through the SYNAPSE (R01 AG062285), Wisconsin ADRC (P30 AG062715), and WRAP (R01 AG027161) studies. Funding was also provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54 HD090256), as well as an instrumentation grant from the NIH Office of the Director (S10 OD025245).