ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes

Rawat, Varun; Wang, Shaowei; Sima, Jian; Bar, Roni; Liraz, Ori; Gundimeda, Usha; Parekh, Trusha; Chan, Jamie; Johansson, Jan O.; Tang, Chongren; Chui, Helena C.; Harrington, Michael G.; Michaelson, Daniel M.; Yassine, Hussein N.

doi:10.1523/jneurosci.1400-19.2019

Cited by 104 publications

(119 citation statements)

References 41 publications

(61 reference statements)

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“…At the low pH of endosomes, apoE4 is more favored than apoE3 to form a molten globule with its increased binding affinity to lipids (Morrow et al, 2002). ApoE aggregation has a role in neurodegenerative diseases such as AD (Rawat et al, 2019), predisposing the aggregation of interacting proteins, e.g., seeding of Aβ fibrils.…”

Section: Apoe Structure and Functionmentioning

confidence: 99%

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

Yassine

Finch

2020

Front. Aging Neurosci.

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The APOE gene alleles modify human aging and the response to the diet at many levels with diverse pleotropic effects from gut to brain. To understand the interactions of APOE isoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction. The age-accelerating APOE4 allele alters the endosomal trafficking of cell surface receptors that mediate lipid and glucose metabolism. The APOE4 allele is the ancestral human allele, joined by APOE3 and then APOE2 in the human species. Under conditions of high infection, uncertain food, and shorter life expectancy, APOE4 may be adaptive for reducing mortality. As humans transitioned into modern less-infectious environments and longer life spans, APOE4 increased risks of aging-related diseases, particularly impacting arteries and the brain. The association of APOE4 with glucose dysregulation and body weight promotes many aging-associated diseases. Additionally, the APOE gene locus interacts with adjacent genes on chromosome 19 in haplotypes that modify neurodegeneration and metabolism, for which we anticipate complex gene-environment interactions. We summarize how diet and Alzheimer's disease (AD) risk are altered by APOE genotype in both animal and human studies and identify gaps. Much remains obscure in how APOE alleles modify nutritional factors in human aging. Identifying risk variant haplotypes in the APOE gene complex will clarify homeostatic adaptive responses to environmental conditions.

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Section: Apoe Structure and Functionmentioning

confidence: 99%

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

Yassine

Finch

2020

Front. Aging Neurosci.

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“…It has further been shown that CS-6253 improved APOE lipidation, reduced amyloid and tau pathology, and mitigated APOE4-driven cognitive impairment in mice [163]. In a recent study, Rawat et al [209] reported that treatment with CS-6253 stabilizes membrane ABCA1 and promotes ABCA1 recycling in primary APOE4 astrocytes. These effects led to increased lipidation and decreased aggregation of APOE4.…”

Section: Apoe Mimetic Peptidesmentioning

confidence: 96%

The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

Chernick

Zhong

2020

Biomolecules

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The role of high-density lipoproteins (HDL) in the cardiovascular system has been extensively studied and the cardioprotective effects of HDL are well established. As HDL particles are formed both in the systemic circulation and in the central nervous system, the role of HDL and its associated apolipoproteins in the brain has attracted much research interest in recent years. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, for which there currently exists no approved disease modifying treatment. Multiple lines of evidence, including a number of large-scale human clinical studies, have shown a robust connection between HDL levels and AD. Low levels of HDL are associated with increased risk and severity of AD, whereas high levels of HDL are correlated with superior cognitive function. Although the mechanisms underlying the protective effects of HDL in the brain are not fully understood, many of the functions of HDL, including reverse lipid/cholesterol transport, anti-inflammation/immune modulation, anti-oxidation, microvessel endothelial protection, and proteopathy modification, are thought to be critical for its beneficial effects. This review describes the current evidence for the role of HDL in AD and the potential of using small peptides mimicking HDL or its associated apolipoproteins (HDL-mimetic peptides) as therapeutics to treat AD.

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“…A recent study comparing ApoE3 with E4 showed that ApoE4 had a greater ABCA1 binding affinity in CNS astrocytes (ApoE2 was not studied) (85). Genetic variants in ABCA1 are also implicated in AMD (8), and mouse models with RPE-specific deletion of ABCA1 show RPE atrophy and retinal degeneration (12).…”

Section: Accumulation Of Lipid Droplets Autophagic Defects and Mitocmentioning

confidence: 99%

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

Cunza

Tan

Thamban

et al. 2020

Preprint

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The retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer’s disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis.

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ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes

Cited by 104 publications

References 41 publications

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

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