Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Arendt, Thomas; Schindler, Cornelia; Brückner, Martina K.; Eschrich, Klaus; Bigl, Volker; Zedlick, Dyrk; Marcova, Lena

doi:10.1523/jneurosci.17-02-00516.1997

Cited by 306 publications

(190 citation statements)

References 111 publications

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“…Furthermore, despite a 60% loss of AchE-positive neurons in the basal forebrain, ChAT activity in the hippocampus and cortex of e4 noncarrier AD subjects was relatively similar to that of e4 noncarrier controls. Similar results were reported by Arendt et al (1997). In a post-mortem study of nondemented subjects, Allen et al (1997) showed significantly greater reductions in ChAT activity in the temporal cortex of e4 carriers compared to e4 noncarriers.…”

Section: Introductionsupporting

confidence: 82%

“…Post-mortem brain tissue samples from AD patients who are e4 carriers have shown greater reductions in choline acetyltranferase (ChAT) activity, a cholinergic marker enzyme, in the hippocampus (Poirier, 1994;Allen et al, 1997), temporal cortex and nucleus basalis of Meynert (NBM) (Arendt et al, 1997), and the frontal cortex (Soininen et al, 1995). Other reports have also pointed to greater reductions in ChAT activity in AD patients homozygous for the e4 allele (e4/e4) in the hippocampus (Poirier, 1994) and the frontal cortex (Soininen et al, 1995) than AD patients who were heterozygous (ie e4/e3 or e4/e2).…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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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“…12 The abnormalities of the neuronal dendrites and their synaptic spines reported in neurological cretinism bear a striking resemblance to those reported in Alzheimer's disease especially among APOE ⑀4 carriers. 13 Similar changes are reported in APOE knockout mice, and also when the human ApoE ⑀4 transgene is introduced into APOE null mice. 14 ApoE has a thyroid hormone (T4) binding domain, and may be involved in transport of T4 into cells.…”

Section: Introductionsupporting

confidence: 54%

“…Autopsies of human fetal brain from iodine-deficient areas are desirable but difficult to organize. It will be interesting to determine whether fetal iodine deficiency has a disproportionate effect upon the behavioral and neurological phenotype in strains of APOE null mice, 13 or mice where a human ⑀4 transgene has been introduced. 14 Neuropathological studies on these mice may also demonstrate increased abnormalities of neuronal differentiation and dendrite branching resembling endemic cretinism.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E is a genetic risk factor for fetal iodine deficiency disorder in China

et al. 2000

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Fetal iodine deficiency disorder (FIDD) is the principal form of endemic cretinism, and the most common cause of preventable mental deficiency in the world. However not everyone at risk develops FIDD and familial aggregation is common. This suggests that genetic factors may also be involved. The Apolipoprotein E (APOE) gene encodes for a lipoprotein that possesses a thyroid hormone binding domain, and APOE genotype may affect the efficiency with which thyroid hormone influences neuronal cell growth during the first and second trimesters of fetal development. We have compared ApoE genotypes in 91 FIDD cases with 154 local control subjects, recruited from three iodine deficiency areas in central China. We have also genotyped 42 FIDD family cases and 158 normal individuals from the families of local controls, and 375 population controls from Shanghai. APOE ⑀4 genotypes were significantly enriched in FIDD probands from each of the three iodine deficiency areas; the ⑀4 allele frequency was 16% vs 6% in controls. The same effect was also observed when we compared FIDD family cases with controls and control families. Our data suggest that in iodine-deficient areas, the APOE ⑀4 allele is a genetic risk factor for FIDD. The phenomenon may affect population selection and contribute to the low frequency of the ⑀4 allele in Chinese compared to Caucasian populations. Molecular Psychiatry (2000) 5, 363-368.

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“…ApoE is also involved in the response to neural injury (43,58,59), maintenance of dendritic arborizations (60), and neuronal remodeling in vitro (61,62) and in AD (63). The recent association of different polymorphisms in the promoter region with AD (32-35) strongly suggests that transcriptional regulation of APOE gene may play an important role in the development of this deleterious disease.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors Zic1 and Zic2 Bind and Transactivate the Apolipoprotein E Gene Promoter

Salero¹,

Pérez-Sen²,

Aruga³

et al. 2001

Journal of Biological Chemistry

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We have used the yeast one-hybrid system to identify transcription factors that bind to specific sequences in proximal regions of the apolipoprotein E gene promoter. The sequence between ؊163 and ؊124, that has been previously defined as a functional promoter element, was used as a bait to screen a human brain cDNA library. Ten cDNA clones that encoded portions of the human Zic1 (five clones) and Zic2 (five clones) transcription factors were isolated. Electrophoretic mobility shift assays confirmed the presence of a binding site for Zic1 and Zic2 in the ؊136/؊125 region. Displacement of binding with oligonucleotides derived from adjacent sequences within the APOE promoter revealed the existence of two additional Zic-binding sequences in this promoter. These sequences were identified by electrophoretic mobility shift assays and mutational analysis in regions ؊65/؊54 and ؊185/؊174. Cotransfection of Zic1 and Zic2 expression vector and different APOE promoter-luciferase reporter constructs in U87 glioblastoma cell line showed that the three binding sites partially contributed to the trans-stimulation of the luciferase reporter. Ectopic expression of Zic1 and Zic2 in U87 cells also trans-stimulated the expression of the endogenous gene, increasing the amount of apolipoprotein E produced by glial cells. These data indicate that Zic proteins might contribute to the transcriptional activity of the apolipoprotein E gene and suggest that apolipoprotein E could mediate some of the developmental processes in which Zic proteins are involved.

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Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Cited by 306 publications

References 111 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 E is a genetic risk factor for fetal iodine deficiency disorder in China

Transcription Factors Zic1 and Zic2 Bind and Transactivate the Apolipoprotein E Gene Promoter

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