ApoE genotype and survival from intracerebral haemorrhage

Alberts, M; Graffagnino, Carmen; McClenny, C.; DeLong, David M.; Strittmatter, Warren J.; Saunders, A.; Roses, A D

doi:10.1016/s0140-6736(95)91411-0

Cited by 283 publications

(146 citation statements)

References 3 publications

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“…More specifically, the benzodiazepine effect that differentiated between the e4 and the non-e4 groups was seen on measures of long-term memory 5 h after the treatment was administered. Thus, the decreased recovery that we observed in the e4 participants following acute administration of two classes of treatments with relatively distinct pharmacological actions is consistent with other findings and suggest that the e4 allele is associated with a general vulnerability of the brain to recover from various pharmacological and neurological insults (Alberts et al, 1995;Friedman et al, 1999;Mayeux et al, 1996;Sorbi et al, 1995).…”

Section: Discussionsupporting

confidence: 91%

Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-ɛ4 Allele in the Elderly: A Controlled Pilot Study

Pomara

Willoughby

Wesnes³

et al. 2003

Neuropsychopharmacol

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The degree to which elderly adults experience cognitive impairments from centrally acting anticholinergic drugs is variable, but the cause of this variability is unknown. The present study examined the e4 allele as a possible modulator of the effects of trihexyphenidyl hydrochloride (Artane t ), an anticholinergic drug, on memory functioning. Of the 24 cognitively intact, elderly participants (age range 62-76), 12 who possessed the e4 allele, participated in a double-blind, randomized, placebo-controlled, crossover, three-way study. All participants were tested after receiving a single oral dose of trihexyphenidyl (1 or 2 mg) or placebo, with a 7-day washout period between sessions. Memory and psychomotor tests were administered at baseline, and at 1, 2.5, and 5 h post-treatment. Results showed that participants with the e4 allele demonstrated significant impairments in delayed recall after both 1 and 2 mg doses of trihexyphenidyl while the non-e4 group did not. Additionally, while acute administration of the 2 mg dose significantly impaired total recall in both e4 and non-e4 carriers, the e4 carriers showed a more persistent impairment. These findings held when participants with the e2 allele were excluded from the analyses. The e4 groups did not differ with respect to psychomotor performance or plasma drug levels. These results provide evidence suggesting that the e4 allele plays a significant role in increasing cognitive sensitivity to trihexyphenidyl and that a temporal component of memory consolidation may be especially vulnerable. A larger study is warranted to confirm these preliminary findings.

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Section: Discussionsupporting

confidence: 91%

Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-ɛ4 Allele in the Elderly: A Controlled Pilot Study

Pomara

Willoughby

Wesnes³

et al. 2003

Neuropsychopharmacol

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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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“…In addition, the q4 allele is associated with increased morbidity following cerebral hemorrhage (Alberts et al, 1995) and head trauma (Chapman et al, 2001b) as well as more rapid progression of disease in patients with multiple sclerosis (Chapman et al, 2001a). A large body of evidence suggests that at least part of the effect of APOE isoforms on AD and CAA risk is mediated by interactions of apoE with the amyloid-h (Ah) peptide, the primary constituent of amyloid plaques that accumulate in the brain of AD patients (reviewed in Holtzman, 2001).…”

Section: Introductionmentioning

confidence: 99%

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Morikawa

Fryer

Sullivan

et al. 2005

Neurobiology of Disease

122

127

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The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have distinct properties from apoE derived from other sources. To develop an efficient system to produce astrocyte-derived apoE in large quantities, we produced and characterized immortalized cell lines from primary astrocyte cultures derived from human APOE knock-in mice. APOE2, APOE3, and APOE4 expressing cell lines were established that secrete apoE in HDL-like particles at similar levels, cholesterol composition, and size as those produced by primary astrocytes. In physiological buffers, astrocyte-secreted apoE3 and E4 associated equally well with amyloid-B. Under the same conditions, only a small fraction of AB formed sodium dodecyl sulfate (SDS)-stable complexes with apoE (E3 N E4). These immortalized astrocytes will be useful for studying mechanisms underlying the isoform-specific effects of apoE in the CNS. D 2004 Elsevier Inc. All rights reserved.

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ApoE genotype and survival from intracerebral haemorrhage

Cited by 283 publications

References 3 publications

Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-ɛ4 Allele in the Elderly: A Controlled Pilot Study

Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-ɛ4 Allele in the Elderly: A Controlled Pilot Study

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

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

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