APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

Blanchard, Joel; Akay, Leyla Anne; Dávila-Velderrain, José; Maydell, Djuna von; Mathys, Hansruedi; Davidson, Shawn M.; Effenberger, Audrey H.; Chen, Chih-Yu; Maner-Smith, Kristal; Hajjar, Ihab; Ortlund, Eric A.; Bula, Michael; Agbas, Emre; Ng, Ayesha P.; Jiang, Xueqiao; Kahn, Martin; Blanco‐Duque, Cristina; Lavoie, Nicolas; Liu, Liwang; Reyes, Ricárdo; Lin, Yong; Ko, Tak; R’Bibo, Lea; Ralvenius, William T.; Bennett, David A.; Cam, Hugh P.; Kellis, M; Tsai, Li‐Huei

doi:10.1038/s41586-022-05439-w

Cited by 217 publications

(207 citation statements)

References 43 publications

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“…It is thus possible that the cause of cortical projection neuron loss in TDPhigh donors is the lack of sufficient mature oligodendrocytes, which are essential for neuron myelination and metabolic support. The impairment of myelination is not limited to C9orf72 FTD-TDP pathology as downregulation of myelin-associated genes is also observed in the prefrontal cortex of patients with AD pathology 87,88 . In AD donors carrying two copies of the APOE4 variant, cholesterol homeostasis is responsible for the downregulation of myelin-associated genes in oligodendrocytes 88 .…”

Section: Discussionmentioning

confidence: 99%

pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex ofC9orf72ALS/FTD patients

Wang

Veire

Gendron

et al. 2023

Preprint

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Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during disease progression. These alterations include downregulation of nuclear and mitochondrial ribosomal protein genes in early disease stages that become upregulated as the disease progresses. High ratios of premature oligodendrocytes expressing low levels of genes encoding major myelin protein components are characteristic of late disease stages and may represent a unique signature of C9orf72 ALS/FTD. Microglia with increased reactivity and astrocyte specific transcriptome changes in genes involved in glucose/glycogen metabolism are also associated with disease progression. Late stages of C9orf72 ALS/FTD correlate with sequential changes in the regulatory landscape of several genes in glial cells, namely MBP/MAG/MOG in oligodendrocytes, CD83/IRF8 in microglia, and GLUT1/GYS2/AGL in astrocytes. Only layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 are significantly reduced in C9orf72 ALS/FTD patients with respect to controls. Our findings reveal previously unknown progressive functional changes in cortical cells of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.

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Section: Discussionmentioning

confidence: 99%

pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex ofC9orf72ALS/FTD patients

Wang

Veire

Gendron

et al. 2023

Preprint

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“…We hypothesise that the APOE effect on weight loss may act through cholesterol- and lipid-metabolism pathways that partly determine response to dietary and environmental factors, as seen in mouse models 96, 97 . Indeed, it has recently been suggested that APOE -mediated cholesterol dysregulation in the brain may influence the onset and severity of Alzheimer’s disease 98 , suggesting that ageing-associated systemic aberrations in cholesterol homeostasis could have far-ranging consequences from weight loss to cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

The genetic architecture of changes in adiposity during adulthood

Venkatesh

Ganjgahi

Palmer

et al. 2023

Preprint

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Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 1.5 million primary-care health records in over 177,000 individuals in UK Biobank to study the genetic architecture of weight-change. Using multiple BMI measurements over time increases power to identify genetic factors affecting baseline BMI. In the largest reported genome-wide study of adiposity-change in adulthood, we identify novel associations with BMI-change at six independent loci, including rs429358 (a missense variant in APOE). The SNP-based heritability of BMI-change (1.98%) is 9-fold lower than that of BMI, and higher in women than in men. The modest genetic correlation between BMI-change and BMI (45.2%) indicates that genetic studies of longitudinal trajectories could uncover novel biology driving quantitative trait values in adulthood.

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“…APOE ε4 allele carriers, the strongest genetic factor known to increase the risk of late-onset AD [ 104 , 105 ], have also shown microstructural WM changes in the fornix at pre-symptomatic phases of the disease [ 59 , 94 ]. In this case, the aberran deposition of cholesterol in oligodendrocytes and the reduced axonal myelination, suposedly caused by cholesterol homeostasis and transport dysregulation, could be a major factor of WM degeneration and loss of function [106] .…”

Section: Changes In Fornix Microstructure An Early Event In Admentioning

confidence: 99%