People with the APOE2 type of the apolipoprotein E gene tend to live longer and have a lower risk of Alzheimer’s disease. Scientists have known about its benefits for years, but the biological reasons behind it remained unclear.
A new study from the Buck Institute on Aging, published in the journal Aging Cell, suggests that APOE2 protects neuronal DNA and helps stave off aging. Senescence, a state in which cells become damaged and dysfunctional, is common with age and is thought to contribute to neurodegeneration.
This result indicates that APOE has a role beyond its well-known involvement in cholesterol transport. They suggest that different versions of genes may also influence how well brain cells store and repair their genetic material over time.
“We’ve known for years that APOE2 carriers tend to live longer and have a lower risk of Alzheimer’s disease, but their defense mechanisms have been a black box,” says lead author Lisa M. Ellerbee, Ph.D., a professor at the Buck Institute. “Our research shows that APOE2 neurons are excellent at preventing and repairing DNA damage and resisting the cellular aging programs that cause much of the decline in later life. Our findings point to entirely new therapeutic directions.”
Comparison of three APOE variants
There are three common forms of APOE: APOE2, APOE3, and APOE4. Although these versions differ by just two amino acids, their effects on brain aging are very different.
APOE4 is the strongest known genetic risk factor for late-onset Alzheimer’s disease (usually after age 65). In contrast, APOE2 has repeatedly been associated with longer lifespan and lower dementia risk in population studies.
To study how APOE variants affect neuronal aging, the researchers used human induced pluripotent stem cells (iPSCs) that were genetically engineered to differ only at the APOE locus.
The research team turned these cells into two types of neurons. One group consisted of inhibitory GABAergic neurons and the other group consisted of excitatory glutamatergic neurons. The researchers then compared how APOE2, APOE3, and APOE4 affected each cell type.
They also studied hippocampal tissue from older mice that had been engineered to carry the human APOE2, APOE3, or APOE4 genes.
APOE2 neurons have less DNA damage
The researchers found that APOE2 neurons accumulated less damage in their DNA.
Bulk and single-cell RNA sequencing showed that APOE2 GABAergic neurons potently activate pathways involved in DNA repair and damage response. APOE4 neurons, on the other hand, showed patterns of gene activity associated with Alzheimer’s disease.
Direct measurements of DNA strand breaks confirmed these findings. APOE2 neurons had significantly less DNA damage than neurons with other genetic mutations.
Brain cells resist cellular aging
APOE2 neurons also appear to be more resistant to aging.
The researchers exposed excitatory neurons to radiation or the chemotherapy drug doxorubicin, both of which can damage DNA and put cells under severe stress. APOE2 neurons showed lower levels of senescence markers (including p16 and CRYAB) than APOE3 and APOE4 neurons.
They also have smaller nucleoli and better preserved nuclear architecture, both of which indicate that cells maintain a healthier internal structure.
APOE2 protein may convey some protection
The researchers also tested whether APOE2’s protective effects benefit neurons that carry APOE4.
When recombinant APOE2 protein was added to APOE4 neurons, the cells showed decreased DNA damage signaling after radiation exposure. The results are an early indication that at least some of APOE2’s protective effects are not limited to people born with the gene mutation, but may be transferable.
Similar signs appear in mouse brains
A similar pattern was obtained in mouse experiments.
Older APOE2 knock-in mice had smaller nucleoli, higher levels of the nuclear scaffolding proteins lamin A/C, and better preserved heterochromatin in the hippocampus than mice with APOE3 or APOE4.
These characteristics are associated with healthier aging of brain cells, further corroborating the results of human neuron experiments.
A new perspective on APOE and brain aging
DNA damage and cellular senescence are increasingly recognized as major causes of aging and age-related diseases, including Alzheimer’s disease.
“Up until now, the APOE field has focused primarily on lipid handling and the biology of amyloid beta,” says Ellerbee. “By showing that the APOE allele also modulates how neurons defend their genomes, this study links a key longevity gene to two of the most actively studied hallmarks of aging.”
Ellerbee said the discovery raises the possibility that treatments designed to improve DNA repair or remove senescent cells from the brain could recapitulate some of APOE2’s natural benefits. Such a strategy could ultimately help people who carry high-risk APOE4 variants.
“What surprised us was how consistent the picture was across two very different neuron types, and across human cells and mouse brain tissue,” said co-first author Cristian Geronimo Olvera, Ph.D., a postdoctoral fellow in the Buck Institute. “APOE2 neurons are not only less damaged at baseline, but also recover more quickly under stress.”
Future treatments inspired by APOE2
Researchers say it is still unclear exactly how APOE2 stabilizes the nuclear envelope and enhances DNA repair.
Future studies will investigate whether APOE2-mimetic compounds or targeted DNA repair treatments can provide similar protection for APOE4 patients, the group at highest genetic risk for Alzheimer’s disease.
Other collaborators include Steven M. Scherer, Carlos Galicia Aguirre, Genesis Vega-Holmazabal, Daniela Garcia, Long Wu, Natalia Murad, Kevin Schneid, Kenneth A. Wilson, Nicola T. Markov, | Jesse Simmons, Akos A. Gerenser, Emily Parlan, Eric Vardin, Judith Campisi, Tara E. Tracy, David Fuhrman, Simon Meroff, Buck Institute. Sicheng Song and Sean D. Mooney, Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA.
This research was supported by a CatalystX award from the National Institute on Aging (R01AG061879, P01AG066591, T32 AG000266), the Paul F. Glenn Center for the Biology of Aging, the Evolution Foundation (HF-PART-23-1422047), and an Alex and Bob Griswold and Valley Foundation Fellowship.
