In the brain of a person with Alzheimer’s disease, neurons degenerate and die, slowly eliminating memories and cognitive skills. However, not all neurons are impacted equally. Some types of neurons in certain brain regions are more susceptible, and even among those subtypes—mysteriously—some perish and some do not.

Researchers at Gladstone Institutes have uncovered molecular clues that help explain what makes some neurons more susceptible than others in Alzheimer’s disease. In a study published in the journal Nature Neuroscience, the scientists present evidence that neurons with high levels of the protein apolipoprotein E (apoE) are more sensitive to degeneration, and that this susceptibility is linked to apoE’s regulation of immune-response molecules within neurons.

This is the first time such a link has been established, which is quite exciting and could open new paths to developing treatments for Alzheimer’s disease.
Gladstone Senior Investigator Yadong Huang, MD, PhD, senior author of the study.

ApoE has long been a focus of Alzheimer’s disease research because people carrying a gene that produces a particular form of apoE (called apoE4) have a higher risk of developing the disease. For this study, Huang and his team harnessed recent advancements in single-cell analysis to study the potential role of apoE in the variable susceptibility of neurons in Alzheimer’s disease.

The team found that, in brain tissue, the proportion of neurons expressing high levels of apoE and MHC-I genes fluctuates in a way that closely matches neurodegeneration and the progression of Alzheimer’s disease.

They observed this relationship both in mouse models of Alzheimer’s disease and in human brain tissue at different stages of neurodegeneration. Their work also revealed a causal link between the expression of MHC-I induced by apoE and the increase in tangled aggregates of a protein called tau, which is a hallmark of Alzheimer’s disease and is a good predictor of neurodegeneration.

The study shows that neurons carrying the form of apoE associated with increased risk of Alzheimer’s disease, apoE4, are particularly susceptible to these stressors. This excess apoE turns on the expression of MHC-I, marking these neurons for destruction. Meanwhile, neurons with lower levels of apoE remain unharmed. Consequently, this process results in selective neurodegeneration within a given neuron type in Alzheimer’s disease, guided by the level of apoE.

Further research could help clarify how apoE and MHC-1 determine which neurons die and which survive in Alzheimer’s disease.

Additional studies could reveal potential new targets for treatments that may be able to disrupt this destructive process in Alzheimer’s disease and potentially in other neurodegenerative disorders as well
Yadong Huang.


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