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Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern.
Neuroscience 2006; 141(3):1149-62N

Abstract

Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation.

Authors+Show Affiliations

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16753269

Citation

Melnikova, T, et al. "Cycloxygenase-2 Activity Promotes Cognitive Deficits but Not Increased Amyloid Burden in a Model of Alzheimer's Disease in a Sex-dimorphic Pattern." Neuroscience, vol. 141, no. 3, 2006, pp. 1149-62.
Melnikova T, Savonenko A, Wang Q, et al. Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern. Neuroscience. 2006;141(3):1149-62.
Melnikova, T., Savonenko, A., Wang, Q., Liang, X., Hand, T., Wu, L., ... Andreasson, K. I. (2006). Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern. Neuroscience, 141(3), pp. 1149-62.
Melnikova T, et al. Cycloxygenase-2 Activity Promotes Cognitive Deficits but Not Increased Amyloid Burden in a Model of Alzheimer's Disease in a Sex-dimorphic Pattern. Neuroscience. 2006 Sep 1;141(3):1149-62. PubMed PMID: 16753269.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern. AU - Melnikova,T, AU - Savonenko,A, AU - Wang,Q, AU - Liang,X, AU - Hand,T, AU - Wu,L, AU - Kaufmann,W E, AU - Vehmas,A, AU - Andreasson,K I, Y1 - 2006/06/06/ PY - 2005/10/25/received PY - 2006/03/30/revised PY - 2006/05/01/accepted PY - 2006/6/7/pubmed PY - 2006/10/19/medline PY - 2006/6/7/entrez SP - 1149 EP - 62 JF - Neuroscience JO - Neuroscience VL - 141 IS - 3 N2 - Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/16753269/Cycloxygenase_2_activity_promotes_cognitive_deficits_but_not_increased_amyloid_burden_in_a_model_of_Alzheimer's_disease_in_a_sex_dimorphic_pattern_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(06)00621-X DB - PRIME DP - Unbound Medicine ER -