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Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease.

ABSTRACT: APOE and Trem2 are major genetic risk factors for Alzheimer's disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.

SUBMITTER: Fitz NF

PROVIDER: S-EPMC8184801 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease.

Fitz Nicholas F NF Nam Kyong Nyon KN Wolfe Cody M CM Letronne Florent F Playso Brittany E BE Iordanova Bistra E BE Kozai Takashi D Y TDY Biedrzycki Richard J RJ Kagan Valerian E VE Tyurina Yulia Y YY Han Xianlin X Lefterov Iliya I Koldamova Radosveta R

Nature communications 20210607 1

APOE and Trem2 are major genetic risk factors for Alzheimer's disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, an ...[more]

PMID: 34099706

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Project description:BackgroundAPOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aβ+) remains unclear.MethodsWe analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aβ-, 1323 Aβ+) and tau PET data were available for a subset of 447 participants (55 Aβ-, 392 Aβ+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aβ + CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultsAPOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aβ+ CU, e2 and e4 were associated with reduced (-12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aβ+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aβ+ ADNI participants.ConclusionsAPOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aβ+ individuals.

Project description:BackgroundGenome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models.MethodsWe used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry.ResultsWe found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity.Conclusion25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.

Dataset Information

Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease.

Publications

Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease.

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