APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes
Joel W. Blanchard,Leyla Anne Akay,Jose Davila-Velderrain,Djuna von Maydell,Hansruedi Mathys,Shawn M. Davidson,Audrey H. Effenberger,Chih-Yu Chen,Kristal M. Maner-Smith,Ihab Hajjar,Eric A. Ortlund,Michael Bula,Emre Agbas,Ayesha P. Ng,Xueqiao Jiang,Martin Kahn,C Blanco-Duque,Nicolas Lavoie,Liwang Liu,Ricardo Reyes,Yuan-Ta Lin,Tak Ko,Lea R'Bibo,William T. Ralvenius,David A. Bennett,Hugh P. Cam,Manolis Kellis,Li-Huei Tsai +27 more
TLDR
In this article , a single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers was performed to gain more comprehensive insights into the impact of APOE-4 on the human brain.Abstract:
APOE4 is the strongest genetic risk factor for Alzheimer’s disease1–3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4–8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2–6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease. APOE4 is associated with widespread gene expression changes across all cell types of the human brain, altered cholesterol homeostasis and transport signalling pathways, and decreased myelination in the brain. read more
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Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies
TL;DR: The ApoE4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer's disease (AD), expressed in 40 to 65% of all AD patients as mentioned in this paper .
Journal ArticleDOI
Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review
Rammohan V. Rao,Kaavya G. Subramaniam,Julie Gregory,Aida L. Bredesen,Christine Coward,Sho Okada,Lance Kelly,Dale E. Bredesen +7 more
TL;DR: In this paper , a systematic review of studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline is presented, including diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins.
Journal ArticleDOI
The complex genetic architecture of Alzheimer's disease: novel insights and future directions
Shea J. Andrews,Alan E. Renton,Brian Fulton-Howard,Anna Podlesny-Drabiniok,Edoardo Marcora,Alison Goate +5 more
TL;DR: In this article , a genome-wide association study (GWAS) was conducted to expand the sample sizes and the number of disease susceptibility loci. But, the results of the GWAS showed that the heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies.
Journal ArticleDOI
This is how an Alzheimer’s gene ravages the brain
TL;DR: In this article , a study in cells and mice suggests that the variant APOE4 affects the all-important insulation around nerve cells, which is important for nerve cell survival and survival.
Journal ArticleDOI
Cure of Alzheimer’s Dementia Requires Addressing All of the Affected Brain Cell Types
TL;DR: In this article , the authors used available data to address the brain cells whose functions become changed as a result of the abnormalities, because at least eleven drugs are available from which to formulate a rational therapy to correct those changes.
References
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TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Journal ArticleDOI
Fast, sensitive and accurate integration of single-cell data with Harmony.
Ilya Korsunsky,Nghia Millard,Jean Fan,Kamil Slowikowski,Fan Zhang,Kevin Wei,Yuriy Baglaenko,Michael B. Brenner,Po-Ru Loh,Po-Ru Loh,Po-Ru Loh,Soumya Raychaudhuri +11 more
TL;DR: Harmony, for the integration of single-cell transcriptomic data, identifies broad and fine-grained populations, scales to large datasets, and can integrate sequencing- and imaging-based data.