Cell type-specific roles of APOE4 in Alzheimer disease

Blumenfeld, Jessica; Yip, Oscar; Kim, Min Joo; Huang, Yadong

doi:10.1038/s41583-023-00776-9

Cited by 24 publications

(9 citation statements)

References 208 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We demonstrated that APOE2, -E3 and -E4 iN cells express APOE protein of which a small fraction is secreted. This aligns with the literature showing neuronal expression of APOE under physiological conditions [17][18][19][20] and only 10 % secretion of neuronally produced APOE [4,6]. In response to injury neuronal APOE expression is upregulated as a potentially protective mechanism, however, upregulation of neuronal APOE4 promoted excitotoxic neuronal cell death [17][18][19][20].…”

Section: Discussionsupporting

confidence: 90%

APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

Budny,

Knöpfli,

Meier

et al. 2024

Preprint

View full text Add to dashboard Cite

The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower the AD risk while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons also have been shown as source for APOE. However, little is known about the differential role of the three APOE isoforms for neuronal energy homeostasis. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE-knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins, nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3 and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism.

show abstract

Section: Discussionsupporting

confidence: 90%

APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

Budny,

Knöpfli,

Meier

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Extensive studies have investigated mechanisms of cellular toxicity associated with APOE4 in the context of neurodegeneration and AD. Emerging evidence suggests that neuronal APOE4 may act as a crucial upstream trigger and likely a driver of late-onset AD pathogenesis, leading to downstream neuro-inflammation, glial responses and subsequent neurodegeneration 58 . Our study sheds light on the cellular consequences of neuronal APOE4 expression, revealing not only cell-autonomous effects of APOE4 in promoting neuronal morphological deterioration, mitochondrial dysfunction and lysosomal disruption in neurons, but also cross-tissue actions on proteostatic abnormalities in body wall muscles.…”

Section: Discussionmentioning

confidence: 99%

“…Our study sheds light on the cellular consequences of neuronal APOE4 expression, revealing not only cell-autonomous effects of APOE4 in promoting neuronal morphological deterioration, mitochondrial dysfunction and lysosomal disruption in neurons, but also cross-tissue actions on proteostatic abnormalities in body wall muscles. Neuronal APOE4 inflicts oxidative stress via excess ROS generation and intracellular cholesterol accumulation by multiple mechanisms 58–60 , which may separately and additively lead to the observed cellular defects in C. elegans . Importantly, reduction of cholesterol from dietary sources or amelioration of excess oxidative stress through NAC or HIF-1 stabilization strongly suppressed these defects, providing a causal link from cholesterol to mortality regulation by VHL-HIF.…”

Section: Discussionmentioning

confidence: 99%

Suppressing APOE4-induced mortality and cellular damage by targeting VHL

Jiang,

Cao,

Xue

et al. 2024

Preprint

View full text Add to dashboard Cite

SUMMARYMortality rate increases with age and can accelerate upon extrinsic or intrinsic damage to individuals. Identifying factors and mechanisms that curb population mortality rate has wide-ranging implications. Here, we show that targeting the VHL-1 (Von Hippel– Lindau) protein suppressesC. elegansmortality caused by distinct factors, including elevated reactive oxygen species, temperature, andAPOE4, the genetic variant that confers high risks of neurodegeneration in Alzheimer’s diseases and all-cause mortality in humans. These mortality factors are of different physical-chemical nature, yet result in similar cellular dysfunction and damage that are suppressed by deleting VHL-1.Stabilized HIF-1 (hypoxia inducible factor), a transcription factor normally targeted for degradation by VHL-1, recapitulates the protective effects of deleting VHL-1. HIF-1 orchestrates a genetic program that defends against mitochondrial abnormalities, excess oxidative stress, cellular proteostasis dysregulation, and endo-lysosomal rupture, all events that lead to mortality. Genetic inhibition ofVhlalso alleviates cerebral vascular injury and synaptic lesions inAPOE4mice, supporting an evolutionarily conserved mechanism. Collectively, we identify the VHL-HIF axis as a potent modifier of APOE4 and propose that targeting VHL-HIF in non-proliferative animal tissues may suppress tissue injuries and mortality by broadly curbing cellular damage.

show abstract

“…Genome-wide association studies (GWAS) of late onset AD (LOAD) have revealed genes enriched in both lipid metabolism and innate immunity 2 . APOE is a major LOAD risk gene linked to lipid metabolism and is highly upregulated in human microglia in AD 3,4 . Notably, both postmortem and human iPSC-derived microglia with APOE risk variant ε4 have more lipid droplets, and this accumulation impairs microglia homeostatic functions and leads to a shift towards a proinflammatory state 5 .…”

Section: Introductionmentioning

confidence: 99%

An arrayed CRISPR/Cas9 screen identifies mTORC1 as a regulator of lipid droplet accumulation in APOE E3 and APOE KO iPSC-derived microglia

Meier,

Larsen,

Wanke

et al. 2024

Preprint

View full text Add to dashboard Cite

Variants of the Apolipoprotein E (APOE) gene, particularly the E4 allele, are significantly associated with an increased risk of Alzheimer's Disease and have been implicated in neuroinflammatory processes due to disrupted lipid metabolism. Lipid alterations can manifest in glial cells as an excessive buildup of lipids, potentially contributing to neuroinflammation. In this study, we observed a heightened lipid load in APOE-deficient human induced pluripotent stem cell (iPSC)-derived microglia relative to cells with other APOE isoforms. To explore the mechanisms governing lipid handling within microglia, we established a technique for the nucleofection of CRISPR/Cas9 ribonucleoprotein complexes into iPSC-derived myeloid cells. Utilizing this method, we performed a targeted screen to identify key upstream modifiers in lipid droplet formation. Our findings highlight the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as a pivotal influence on lipid storage in microglia with both APOE3 and APOE knockout genotypes, underscoring its role in lipid dysregulation associated with Alzheimer's Disease and neuroinflammation.

show abstract

Cell type-specific roles of APOE4 in Alzheimer disease

Cited by 24 publications

References 208 publications

APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

Suppressing APOE4-induced mortality and cellular damage by targeting VHL

An arrayed CRISPR/Cas9 screen identifies mTORC1 as a regulator of lipid droplet accumulation in APOE E3 and APOE KO iPSC-derived microglia

Contact Info

Product

Resources

About