Direct Transcriptional Effects of Apolipoprotein E

Theendakara, Veena; Peters‐Libeu, Clare; Spilman, Patricia; Poksay, Karen S.; Bredesen, Dale E.; Rao, Rammohan V.

doi:10.1523/jneurosci.3562-15.2016

Cited by 120 publications

(126 citation statements)

References 55 publications

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“…While the current generation of APOE knock-in mice harbors the human gene sequence, they retain the regulatory elements found in mice. It is critical to address this caveat in rodent studies, in lieu of recent studies including one showing evidence that apoE can act as a transcription factor and influence a wide variety of signaling pathways (205). To circumvent the limitation of existing animal models, new experimental paradigms, particularly those derived from humans (such as iPSCs and brain organoids) need to be developed and characterized.…”

Section: Future Directionsmentioning

confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

176

145

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In 1907, the German psychiatrist, Alois Alzheimer, published a case report, "On an unusual illness of the cerebral cortex," in which he described what we now know as Alzheimer's disease (AD) (1). More than a century after this landmark discovery, AD is now recognized as the most common cause of late-life dementia. AD pathology is characterized by the cerebral accumulation of amyloid plaques and neurofibrillary tangles, both of which consist predominantly of specific insoluble protein aggregates. The majority of AD cases are sporadic and have a relatively late onset, predominantly after the age of 65. This form of AD is known as late-onset AD (LOAD), in contrast to early-onset AD, which has a strong genetic component, is often autosomal dominant, and accounts for less than 1% of AD cases (2). While most genetic risk factors for LOAD identified in the past two decades have a relatively small impact on AD risk, extensive epidemiological, clinical, and pathological studies have established the APOE gene on chromosome 19 as the most important genetic risk factor for developing LOAD (3-5). This locus encodes a 299 amino acid glycoprotein (apoE) that is expressed in several cell types, with highest expression levels found in the liver and the brain, where it is expressed predominantly by astrocytes (6) and, to a lesser extent, microglia (7,8). The human APOE gene Abstract Alzheimer's disease (AD) is one of the fastestgrowing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid- (A). Here, we discuss the role of apoE on the biophysical properties and metabolism of the A peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including A) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond A, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.

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Section: Future Directionsmentioning

confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

176

145

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“…Because of this, they were not able to study the effects of altered TOMM40 mRNA or protein on mitochondrial function. In addition, because all of their study subjects were APOE ε3/ε4 heterozygotes, their results may have reflected contributions of the APOE ε4 allele to the mitochondrial phenotype[18, 54]. Although HeLa cells are also APOE ε3/ε4 , HeLa cells do not express ApoE protein[53], and the exogenous expression system we employed obviated possible transcriptional effects of the endogenous genomic APOE gene on TOM40 expression driven from the exogenous plasmid.…”

Section: Discussionmentioning

confidence: 99%

“…To avert this potential problem, we used a HeLa over-expression system, providing a common genomic background. Although the HeLa APOE/TOMM40 haplotype is APOE ε3/4 S/VL, HeLa cells do not express measurable quantities of ApoE protein[53], and the use of a plasmid DNA expression system obviated potential ‘523’ poly-T- and APOE ε4-mediated gene regulatory effects[54]. …”

Section: Introductionmentioning

confidence: 99%

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Zeitlow

Charlambous

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The neuron-specific regulation of apoE expression demonstrates the critical role of apoE production, presumably for redistribution of cholesterol for cellular repair and maintenance and possibly as a transcription factor. 32 …”

Section: Lipoprotein Synthesis and Metabolism In The Cns In Humansmentioning

confidence: 99%

Central Nervous System Lipoproteins

Mahley

2016

ATVB

334

172

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ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease.

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Direct Transcriptional Effects of Apolipoprotein E

Cited by 120 publications

References 55 publications

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Central Nervous System Lipoproteins

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