Alzheimer’s disease is strongly associated with a genetic variant widely known as APOE4. This is one variation of the APOE gene; the APOE3 variant has been linked to protection from Alzheimer’s. Scientists have now learned more about exactly how the APOE4 variant affects the brain before symptoms of the disease arise. This work could also lead to therapeutics that could reverse those changes. The findings have been reported in Nature Aging.
Previous research has indicated that neuronal hyperactivity occurs in Alzheimer’s patients who are APOE4 carriers.
In this work, the scientists used a mouse model to analyze the impacts of APOE4. In mouse APOE4 carriers, there was an increase in the levels of a protein called Nell2, causing shrinkage and hyperactivity in neurons. The neuronal hyperactivity in the mice happened in the same parts of the brain as it does in Alzheimer’s patients who are APOE4 carriers. As neuronal hyperactivity in early life increased in the mice, so did the severity of their memory problems later in life.
"We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages,” said co-senior study author Misha Zilberter, Ph.D., principal staff research scientist at Gladstone Institutes.
The investigators also used moelcular tools to lower Nell2 levels, and this reversed the neuronal problems. Even in APOE4-carrying adult mice, this method improved neuronal function and restored their normal size.
The study suggested that Nell2 inhibition may be one path forward in the search for effective Alzheimer's treatments, though it would be limited to APOE4 carriers, and more work will be needed to confirm that suggestion.
In mice carrying APOE3, neurons eventually became hyperexcitable, but only in old age. "This suggests APOE4 accelerates a process that resembles normal aging, and could explain why people with the gene variant are more likely to develop Alzheimer's disease earlier in life," said co-senior study author Yadong Huang, MD, Ph.D., associate director of the Gladstone Institute of Neurological Disease.
"This study is a big breakthrough for the field of Alzheimer's research," added Huang.
APOE4 is generally active in astrocytes, which can affect neurons in a variety of ways. "When we deleted the APOE4 gene from astrocytes, nothing changed," noted Zilberter. "But when we deleted it from neurons, the cells became larger and started functioning normally again."
This work seems to show that the impact of APOE4 may ultimately be on neurons.
"What's exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level," Huang said. "That tells us the damage is not irreversible, and that there may be a window for intervention even after disease processes have been triggered."
Sources: Gladstone Institutes, Nature Aging
