By Emily Leclerc | Waisman Science Writer
New research from Waisman investigator, Tracy Hagemann, PhD, associate research professor, delves into the cognitive impairments and associated molecular changes caused by Alexander disease (AxD), revealing similarities to other neurodegenerative diseases like Alzheimer’s. The study highlights the role of astrocyte dysfunction in AxD and its potential implications for broader neurodegenerative research, helping to pave the way for prospective treatment targets and therapeutic strategies.
AxD, a rare genetic neurological condition, has a wide-ranging list of symptoms. Developmental delays and learning deficits have long been a part of that list, but what exactly the cognitive affects look like and what causes them are not well understood. “Often children with AxD have a variety of developmental troubles and if they’re having issues with milestones like growing and walking, or they are having seizures, the cognitive side of things might not be at the forefront for parents and physicians to look into,” says Hagemann. “It’s also difficult to generalize given the rarity and variability of the disease, but that’s likely part of why the cognitive impacts of AxD haven’t been well studied.”
This new study from Hagemann uses their recently developed rodent model to study the cognitive impacts of AxD. A better understanding of how AxD leads to deficits in learning and memory has the potential to identify new targets for treatment and provide relevant ways to measure treatment effectiveness. The paper, “GFAP mutation and astrocyte dysfunction lead to a neurodegenerative profile with impaired synaptic plasticity and cognitive deficits in a rat model of Alexander disease,” was recently published in the journal eNeuro.
AxD is what is known as a leukodystrophy. That is a family of conditions that causes the breakdown of the white matter in the brain. In AxD specifically, this is typically caused by a single mutation in the gene that produces the protein GFAP (glial fibrillary acidic protein) which disrupts the function of astrocyte cells in the brain. Astrocytes are crucially important support cells that help the brain clear out excess neurotransmitters, stabilize and monitor the blood-brain barrier, and promote the formation of synapses, or connections, between neurons. Hagemann and her team wanted to look more closely at how synapse formation was impacted, as the dysregulation or degradation of synapses could contribute to the cognitive deficits seen in AxD. They investigated the synapses in the hippocampus, a part of the brain that is highly connected to memory.
After analyzing gene and protein expression data from their rodent model, they found a significant neuroinflammatory response that happened early in development and progressed with age. Many genes involved in synapse formation and maintenance were less active as well. They also found a significant reduction in the activity of mitochondrial genes, suggesting the brain’s energy supply could be affected. The prolonged inflammatory response combined with impaired astrocyte function in the hippocampus, lead to poorly-maintained and disrupted synapses. The rodent model showed the impact of that by underperforming in memory and learning-based tests.
“When you look at the combined gene expression data, it matches general profiles for other conditions like Alzheimer’s disease and Parkinson’s,” Hagemann says. “It looks like neurodegenerative diseases that are normally associated with aging, but these animals are young. In people, although AxD can be diagnosed later in life, it is often diagnosed in children and infants.”
These similarities raise important questions and implications for Hagemann. Could this be an indication that astrocyte dysfunction might be playing a larger role in conditions like Alzheimer’s disease than is currently thought? “AxD almost looks like premature aging of the central nervous system, which agrees with our earlier work with Mel Feany at Harvard demonstrating that astrocytes in AxD show signs of senescence” Hagemann says. “AxD is caused by GFAP mutations which lead to all these downstream effects. Clearly GFAP is not mutated in Alzheimer’s disease, but astrocytes are reactive with increased GFAP expression, and this work might indicate that loss of normal astrocyte functions, or a gain of detrimental ones, may contribute to neurodegenerative diseases of aging.” While the scope of this study is limited to AxD and the hippocampus, it has the potential to open new research doors for more common diseases as well.
Importantly, the AxD rodent model was able to demonstrate issues in learning and memory that are seen in case studies of the disease in humans. The model was created in 2021 by Hagemann and Waisman investigator Albee Messing, VMD, PhD, professor emeritus of comparative biosciences in collaboration with Robert Berman, PhD, professor emeritus of neurological surgery at the University of California, Davis, and faculty of the M.I.N.D Institute. They continue to characterize the model’s cognitive and motor impairments as well as the model’s ability to accurately reflect the condition as it is seen in people. This study helps to reinforce that the rodent model can provide a good representation of the disease.
There are several different ways this research could evolve from here with many open questions left to answer. How are other cells in the central nervous system impacted and which cell types have decreased mitochondrial function? Is it the inflammatory response that is harming synapses or is it the loss of astrocyte support? Is synaptic function impaired before clinical symptoms? Is it issues just in the hippocampus that account for the cognitive deficits in AxD or do other brain regions contribute? “There’s pathology throughout the brain and the spinal cord in the model, and there is so much more to understand in how mutations that primarily affect astrocytes can lead to impairment and such devastating effects on the central nervous system,” Hagemann says.
Even with all of the unanswered questions and potential research paths, the ultimate goal of Hagemann’s work remains the same – to provide a comprehensive understanding of AxD to allow for the development of future treatments and therapeutics to help those who are diagnosed.
Key Takeaways
- This study provides new insight into the learning and memory deficits caused by Alexander disease, which have historically been poorly characterized due to the disease’s rarity and complexity.
- Impaired astrocyte function in Alexander disease leads to disrupted synaptic support, neuroinflammation, and potentially energy deficits in the brain – particularly in the hippocampus, which is critical for memory.
- The gene expression profile of the Alexander disease rodent model, resembled the profiles of neurodegenerative disease such as Alzheimer’s disease. This suggests that astrocyte dysfunction may play a larger role in these conditions than previously understood.
- This study helps validate and characterize the team’s newer rodent model, showing that it can be a powerful research tool to help understand Alexander disease.