APOE: A potential marker of disease progression in ALS

Lacomblez, Lucette; Doppler, V.; Beucler, I.; Costes, G.; Salachas, François; Raisonnier, A; Forestier, Nadine Le; Pradat, Pierre; Bruckert, Éric; Meininger, Vincent

doi:10.1212/wnl.58.7.1112

Cited by 70 publications

(48 citation statements)

References 7 publications

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“…Specifically, APOE had been linked to Parkinson disease (PD) (149,150), chronic traumatic encephalopathy (151), Huntington disease (152,153), frontotemporal dementia (FTD) (154), and certain subsets of amyotrophic lateral sclerosis (155)(156)(157), though the latter findings conflicted with some other studies (158)(159)(160). Here, we discuss the current state of knowledge on the specific interaction between APOE and the aggregation-prone proteins associated with some of these diseases.…”

Section: Apoe and Other Amyloidogenic Proteinsmentioning

confidence: 95%

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

185

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: Apoe and Other Amyloidogenic Proteinsmentioning

confidence: 95%

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

185

145

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“…In some, 40-80% of patients with AD possess at least one apoE4 allele (12). Likewise, apoE4 is associated with earlier onset, progression, or severity of head trauma (13)(14)(15)(16)(17)(18)(19), stroke (20,21), complications after coronary artery bypass surgery (22,23), Parkinson's disease (24)(25)(26)(27), amyotrophic lateral sclerosis (28)(29)(30)(31)(32), multiple sclerosis (33,34), diabetic neuropathy (35), sleep apnea (36), Lewy body disorders (37), and CNS ischemia (38).…”

Section: Apoe and Neuropathologymentioning

confidence: 99%

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

Proc. Natl. Acad. Sci. U.S.A.

834

801

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The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synaptodendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid ␤ peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N-and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of ''structure correctors'' to convert apoE4 to an ''apoE3-like'' molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and ''mitochondrial protectors'' to prevent cellular energy disruption. mitochondria ͉ neurodegeneration ͉ cytoskeleton ͉ protein folding A polipoprotein (apo) E plays a fundamental role in the maintenance and repair of neurons, but its three isoforms differ in their abilities to accomplish these critical tasks (1-3). ApoE4 is associated with a wide variety of neuropathological processes. We hypothesize that different insults associated with a variety of disorders, in concert with apoE4, can lead to neuropathology. We believe that those processes are mediated by the cellular origin of apoE (astrocytes, neurons, or microglia), the nature of various injurious factors (''second hits''), and the structure of apoE4. Thus, understanding the structure and function of the apoE isoforms will yield new strategies for treating neuropathologies.Although apoE is involved in many neuropathologies, we will focus on its role in Alzheimer's disease (AD). We will consider the unique structural features that distinguish apoE4 from apoE3 and apoE2, the sites of synthesis and normal roles of apoE in the nervous system, and the pathological roles of apoE4 with or without amyloid ␤ (A␤) peptide. The evidence suggests that apoE4 is considerably more than a simple contributing factor in AD pathogenesis. ApoE and NeuropathologyApoE4's involvement in neuropathology is we...

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“…ApoE4 is a major risk factor or susceptibility gene that increases the occurrence and lowers the age of onset of the sporadic and some familial forms of Alzheimer's disease (AD) (Corder et al, 1993;Saunders et al, 1993;Strittmatter et al, 1993). ApoE4 is also associated with earlier onset, progression, or severity of head trauma (Teasdale et al, 1997), stroke (Alberts et al, 1995;Slooter et al, 1997), Parkinson's disease (Li et al, 2004), multiple sclerosis (Schmidt et al, 2002;Kantarci et al, 2004), and amyotrophic lateral sclerosis (Moulard et al, 1996;Lacomblez et al, 2002). Although the mechanisms underlying the pathogenic effects of apoE4 in AD and other neurodegenerative disorders are still poorly understood, emerging data strongly suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to these diseases by interacting with different factors through various pathways (Weisgraber and Mahley, 1996;Huang et al, 2004Huang et al, , 2006aMahley et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS

Xu¹,

Walker²,

Bernardo³

et al. 2008

J. Neurosci.

103

102

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Neuronal expression of apolipoprotein (apo) E4 may contribute to the pathogenesis of Alzheimer's disease (AD). In studying how apoE expression is regulated in neurons, we identified a splicing variant of apoE mRNA with intron-3 retention (apoE-I3). ApoE-I3 mRNA was detected in neuronal cell lines and primary neurons, but not in astrocytic cell lines or primary astrocytes, from humans and mice by reverse transcription (RT)-PCR. In both wild-type and human apoE knock-in mice, apoE-I3 was found predominantly in cortical and hippocampal neurons by in situ hybridization. Cell fractionation and quantitative RT-PCR revealed that over 98% of the apoE-I3 mRNA was retained in the nucleus without protein translation. In transfected primary neurons, apoE expression increased dramatically when intron-3 was deleted from a genomic DNA construct and decreased markedly when intron-3 was inserted into a cDNA construct, suggesting that intron-3 retention/splicing controls apoE expression in neurons. In response to excitotoxic challenge, the apoE-I3 mRNA was markedly increased in morphologically normal hippocampal neurons but reduced in degenerating hippocampal neurons in mice; apoE mRNA showed the opposite pattern. This apparent precursor-product relationship between apoE-I3 and apoE mRNA was supported by a transcriptional inhibition study. Thus, neuronal expression of apoE is controlled by transcription of apoE-I3 under normal conditions and by processing of apoE-I3 into mature apoE mRNA in response to injury.

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APOE: A potential marker of disease progression in ALS

Cited by 70 publications

References 7 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

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS

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