DNA / RNA
Recent research has suggested that the longevity-associated APOE2 gene variant helps human neurons to preserve genome integrity and resist cellular senescence, offering a possible mechanistic explanation for its protective effect against Alzheimer’s disease
People who carry the APOE2 version of the apolipoprotein E gene have been found to be more likely to live to an advanced age and to have partial protection against Alzheimer’s disease, however, scientists have struggled to explain the biological mechanism behind this effect.
Now a study from the Buck Institute for Research on Aging, Novato, California, USA, has suggested that APOE2 helps human neurons to keep their DNA intact and to resist cellular senescence – a damaged and dysfunctional state that accumulates with age and contributes to neurodegeneration.
The findings have shifted attention beyond the established role of apolipoprotein E in the transportation of cholesterol and towards a less recognised function of the gene – its role in how brain cells preserve the integrity of their genome as they age. The work has indicated that APOE2 may support neuronal health by strengthening the cell’s response to DNA damage and by reducing the tendency of neurons to enter senescence, a process increasingly linked with age-related disease.
“We’ve known for years that APOE2 carriers tend to live longer and have a lower risk of Alzheimer’s but the protective mechanism has been [like] a ‘black box’,” said senior author Dr. Lisa M. Ellerby, who is a professor at the Buck Institute.
“Our work shows that APOE2 neurons are better at preventing and repairing DNA damage and they resist the cellular ageing programming that drives so much of late-life decline. Our findings point to entirely novel therapeutic directions,” she said.
Apolipoprotein E exists in three common forms: APOE2, APOE3 and APOE4. These variants differ by just two amino acids but are associated with markedly different outcomes in brain ageing. APOE4 is the strongest known genetic risk factor for late-onset Alzheimer’s disease, which usually develops after the age of 65, while APOE2 has consistently been linked in population studies with exceptional longevity and reduced dementia risk. APOE3 is the most common form and is often regarded as the reference variant against which APOE2 and APOE4 are compared.
To isolate the contribution of apolipoprotein E itself to neuronal ageing, the Buck Institute team used human induced pluripotent stem cells (iPSCs) that had been genetically engineered to differ only at the APOE locus. Induced pluripotent stem cells are adult cells reprogrammed into a stem-cell-like state, from which they can be directed to form different cell types. This approach allowed the researchers to compare the effects of APOE2, APOE3 and APOE4 in a controlled human cellular system.
The researchers generated two types of brain neuron from these cells:
Gamma-aminobutyric acid is the brain’s principal inhibitory neurotransmitter, while glutamate is its principal excitatory neurotransmitter. By studying both cell types, the team could assess whether the effects of APOE variants were restricted to one neuronal population or represented a broader feature of neuronal ageing. The researchers also examined hippocampal tissue from aged mice that carried human APOE2, APOE3 or APOE4. The hippocampus is a brain region central to memory and is particularly vulnerable in Alzheimer’s disease.
The study found that APOE2 neurons accumulated less DNA damage. Bulk and single-cell RNA sequencing showed that APOE2 gamma-aminobutyric acid-ergic neurons strongly upregulated DNA repair and damage-response pathways. By contrast, APOE4 neurons showed transcriptional signatures associated with Alzheimer’s disease. Direct measurements of DNA strand breaks confirmed that APOE2 neurons carried significantly less damage which suggested that the protective variant may help neurons to sustain genome stability during ageing.
The APOE2 neurons also resisted senescence more effectively. When the research team exposed excitatory neurons to stress through radiation or the chemotherapy drug doxorubicin, APOE2 neurons showed lower levels of senescence markers, including p16 and crystallin alpha B. They also had smaller nucleoli and better-preserved nuclear architecture than APOE3 and APOE4 neurons. These features are important because senescent cells can secrete inflammatory and tissue-disruptive signals while disruption to nuclear structure has been associated with cellular ageing and impaired DNA maintenance.
The study also suggested that the protective effect of APOE2 may not be purely genetic. When the researchers added recombinant APOE2 protein to APOE4 neurons, they observed reduced DNA damage signalling after radiation exposure. This provided an early indication that APOE2-related protection might – in principle – be transferable through therapeutic intervention, although the authors cautioned that further research will be needed before such an approach can be considered clinically viable.
Evidence from mouse models supported the observations in human neurons. Aged APOE2 knock-in mice brain tissue showed smaller nucleoli, higher levels of the nuclear scaffolding protein Lamin A/C and better-preserved heterochromatin in the hippocampus than APOE3 or APOE4 mice. Heterochromatin is a tightly packed form of DNA that helps to regulate gene activity and preserve genome stability. These features are associated with healthier brain ageing and provided further evidence that APOE2 may help to maintain the structural integrity of neuronal nuclei.
Cellular senescence and accumulated DNA damage have now been recognised as central drivers of ageing and age-related disease, including Alzheimer’s disease. This study has placed APOE2 within this broader biological framework by linking a major longevity-associated gene to two of the most intensively studied hallmarks of ageing.
“Until now, the APOE field has focused largely on lipid handling and amyloid-beta biology,” said Ellerby.
“By showing that APOE alleles also tune how neurons defend their genome, this study connects a major longevity gene to two of the most actively studied hallmarks of ageing,” she added.
Ellerby said the findings suggested that therapeutic strategies designed to boost DNA repair, or to clear senescent cells, in the brain could mimic some of the natural protection conferred by APOE2. Such approaches could, in future, prove relevant to people who carry the higher-risk APOE4 variant. However, the study remains mechanistic and preclinical and it does not yet establish a treatment for Alzheimer’s.
“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 Dr. Cristian Gerónimo-Olvera, a postdoctoral fellow at the Buck Institute.
“APOE2 neurons aren’t just less damaged at baseline, they recover faster when stressed,” he concluded.
The authors noted that the precise molecular mechanism by which APOE2 stabilises the nuclear envelope and supports DNA repair remains to be defined. Future studies will assess whether APOE2-mimetic compounds or targeted DNA repair therapies can confer similar protection in APOE4 carriers, the population at highest genetic risk for Alzheimer’s disease.
The work has nevertheless offered a clearer biological route through which APOE2 may contribute to longevity and reduced dementia risk, and it has broadened the therapeutic discussion beyond cholesterol metabolism and amyloid-beta to include genome maintenance and cellular senescence.
For further reading please visit: 10.1111/acel.70494
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