Study Explains How Apoe2 Gene Protects The Brain Against Alzheimer's Disease

People who transportation nan APOE2 type of nan apolipoprotein E cistron are much apt to unrecorded to precocious property and are partially protected against Alzheimer's disease, but scientists person struggled to explicate why. A caller study from nan Buck Institute for Research connected Aging, now published successful Aging Cell, offers a mechanistic answer: APOE2 helps quality neurons support their DNA intact and defy becoming senescent, a damaged, dysfunctional authorities that accumulates pinch property and contributes to neurodegeneration.

The findings displacement attraction distant from APOE's well-known domiciled successful cholesterin carrier and toward a antecedently underappreciated usability of nan gene: shaping really encephalon cells support nan integrity of their genome arsenic they age.

 We've known for years that APOE2 carriers thin to unrecorded longer and person a little consequence of Alzheimer's, but nan protective system has been a achromatic box. Our activity shows that APOE2 neurons are amended astatine preventing and repairing DNA damage, and they defy nan cellular aging programme that drives truthful overmuch of late-life decline. Our findings constituent to wholly caller therapeutic directions."

Lisa M. Ellerby, PhD, elder author, professor astatine nan Buck Institute

What nan researchers did

APOE comes successful 3 communal forms, APOE2, APOE3, and APOE4, that disagree by conscionable 2 amino acids. APOE4 is nan strongest known familial consequence facet for late-onset Alzheimer's illness (typically aft property 65), while APOE2 is consistently linked successful organization studies to exceptional longevity and reduced dementia risk.

To isolate what APOE itself contributes to neuronal aging, nan Buck squad utilized quality induced pluripotent stem cells (iPSCs) genetically engineered to disagree only astatine nan APOE locus. They generated 2 types of encephalon neurons from these cells, inhibitory GABAergic neurons and excitatory glutamatergic neurons, and compared really nan different APOE versions affected each compartment type. They besides examined hippocampal insubstantial from aged mice carrying nan quality APOE2, APOE3, aliases APOE4 gene.

Key findings

APOE2 neurons accumulate little DNA damage. Bulk and single-cell RNA sequencing showed that APOE2 GABAergic neurons powerfully upregulate DNA repair and damage-response pathways, while APOE4 neurons show transcriptional signatures associated pinch Alzheimer's disease. Direct measurements of DNA strand breaks confirmed that APOE2 neurons carried importantly little damage.

APOE2 neurons defy becoming senescent. When nan squad stressed excitatory neurons pinch radiation aliases nan chemotherapy supplier doxorubicin, APOE2 neurons showed little levels of senescence markers (including p16 and CRYAB), smaller nucleoli, and better-preserved atomic architecture compared pinch APOE3 and APOE4 neurons.

APOE2 macromolecule tin protect APOE4 neurons. Adding recombinant APOE2 macromolecule to APOE4 neurons reduced DNA harm signaling aft radiation, an early hint that nan protective effect mightiness beryllium transferable, not conscionable genetic.

The rodent encephalon agrees. Aged APOE2 knock-in mice showed smaller nucleoli, higher levels of nan atomic scaffolding macromolecule Lamin A/C, and better-preserved heterochromatin successful nan hippocampus than APOE3 aliases APOE4 mice, features associated pinch healthier encephalon aging.

Why it matters

Cellular senescence and accumulated DNA harm are now recognized arsenic cardinal drivers of aging and age-related disease, including Alzheimer's. "Until now, nan APOE section has focused mostly connected lipid handling and amyloid-beta biology," says Ellerby. "By showing that APOE alleles besides tune really neurons take sides their genome, this study connects a awesome longevity cistron to 2 of nan astir actively studied hallmarks of aging."

Ellerby says nan activity suggests that strategies aimed astatine boosting DNA repair aliases clearing senescent cells successful nan encephalon could mimic immoderate of nan earthy protection conferred by APOE2, perchance benefiting group who transportation nan higher-risk APOE4 variant.

 "What amazed america was really accordant nan image was crossed 2 very different neuron types and crossed quality cells and rodent encephalon tissue," said co-first writer Cristian Gerónimo-Olvera, PhD, a postdoctoral chap astatine nan Buck Institute. "APOE2 neurons aren't conscionable little damaged astatine baseline, they retrieve faster erstwhile stressed."

Next steps

The authors statement that nan precise molecular system by which APOE2 stabilizes nan atomic letter cover and supports DNA repair remains to beryllium defined. Future studies will research whether APOE2-mimetic compounds aliases targeted DNA repair therapies tin confer akin protection successful APOE4 carriers, nan organization astatine highest familial consequence for Alzheimer's disease.