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Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele.
Acta Neuropathol 2003; 105(1):25-9AN

Abstract

The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production.

Authors+Show Affiliations

Neuropathologic Institute, UniversitätsSpital Zürich, Schmelzbergstrasse 12, 8091 Zürich, Switzerland. jens.pahnke@web.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12471457

Citation

Pahnke, J, et al. "Cerebral Beta-amyloid Deposition Is Augmented By the -491AA Promoter Polymorphism in Non-demented Elderly Individuals Bearing the Apolipoprotein E Epsilon4 Allele." Acta Neuropathologica, vol. 105, no. 1, 2003, pp. 25-9.
Pahnke J, Walker LC, Schroeder E, et al. Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele. Acta Neuropathol. 2003;105(1):25-9.
Pahnke, J., Walker, L. C., Schroeder, E., Vogelgesang, S., Stausske, D., Walther, R., & Warzok, R. W. (2003). Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele. Acta Neuropathologica, 105(1), pp. 25-9.
Pahnke J, et al. Cerebral Beta-amyloid Deposition Is Augmented By the -491AA Promoter Polymorphism in Non-demented Elderly Individuals Bearing the Apolipoprotein E Epsilon4 Allele. Acta Neuropathol. 2003;105(1):25-9. PubMed PMID: 12471457.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele. AU - Pahnke,J, AU - Walker,L C, AU - Schroeder,E, AU - Vogelgesang,S, AU - Stausske,D, AU - Walther,R, AU - Warzok,R W, Y1 - 2002/11/05/ PY - 2002/02/18/received PY - 2002/06/20/revised PY - 2002/07/04/accepted PY - 2002/12/10/pubmed PY - 2003/4/4/medline PY - 2002/12/10/entrez SP - 25 EP - 9 JF - Acta neuropathologica JO - Acta Neuropathol. VL - 105 IS - 1 N2 - The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production. SN - 0001-6322 UR - https://www.unboundmedicine.com/medline/citation/12471457/Cerebral_beta_amyloid_deposition_is_augmented_by_the__491AA_promoter_polymorphism_in_non_demented_elderly_individuals_bearing_the_apolipoprotein_E_epsilon4_allele_ L2 - https://dx.doi.org/10.1007/s00401-002-0602-0 DB - PRIME DP - Unbound Medicine ER -