Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model

Chiho Hirata-Fukae; Hui Fang Li; Hyang Sook Hoe; Audrey J. Gray; S. Sakura Minami; Katsuyoshi Hamada; Takako Niikura; Fang Hua; Hiroe Tsukagoshi-Nagai; Yuko Horikoshi-Sakuraba; Mohamed Mughal; G. William Rebeck; Frank M. LaFerla; Mark P. Mattson; Nobuhisa Iwata; Takaomi C. Saido; William L. Klein; Karen E. Duff; Paul S. Aisen; Yasuji Matsuoka

doi:10.1016/j.brainres.2008.03.079

Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model

Chiho Hirata-Fukae, Hui Fang Li, Hyang Sook Hoe, Audrey J. Gray, S. Sakura Minami, Katsuyoshi Hamada, Takako Niikura, Fang Hua, Hiroe Tsukagoshi-Nagai, Yuko Horikoshi-Sakuraba, Mohamed Mughal, G. William Rebeck, Frank M. LaFerla, Mark P. Mattson, Nobuhisa Iwata, Takaomi C. Saido, William L. Klein, Karen E. Duff, Paul S. Aisen, Yasuji Matsuoka^*

^*Corresponding author for this work

Neurobiology

Research output: Contribution to journal › Article › peer-review

206 Scopus citations

Abstract

Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.

Original language	English (US)
Pages (from-to)	92-103
Number of pages	12
Journal	Brain research
Volume	1216
DOIs	https://doi.org/10.1016/j.brainres.2008.03.079
State	Published - Jun 24 2008

Keywords

Alzheimer's disease
Amyloid beta
Beta-secretase
Gender difference
Hyperphosphorylation
Neprilysin
Oligomer
Tau
Transgenic mice

ASJC Scopus subject areas

Neuroscience(all)
Molecular Biology
Clinical Neurology
Developmental Biology

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10.1016/j.brainres.2008.03.079

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Hirata-Fukae, C., Li, H. F., Hoe, H. S., Gray, A. J., Minami, S. S., Hamada, K., Niikura, T., Hua, F., Tsukagoshi-Nagai, H., Horikoshi-Sakuraba, Y., Mughal, M., Rebeck, G. W., LaFerla, F. M., Mattson, M. P., Iwata, N., Saido, T. C., Klein, W. L., Duff, K. E., Aisen, P. S., & Matsuoka, Y. (2008). Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain research, 1216, 92-103. https://doi.org/10.1016/j.brainres.2008.03.079

@article{9b54b53698104da38c6c9dc1b7aef7ce,

title = "Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model",

abstract = "Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.",

keywords = "Alzheimer's disease, Amyloid beta, Beta-secretase, Gender difference, Hyperphosphorylation, Neprilysin, Oligomer, Tau, Transgenic mice",

author = "Chiho Hirata-Fukae and Li, {Hui Fang} and Hoe, {Hyang Sook} and Gray, {Audrey J.} and Minami, {S. Sakura} and Katsuyoshi Hamada and Takako Niikura and Fang Hua and Hiroe Tsukagoshi-Nagai and Yuko Horikoshi-Sakuraba and Mohamed Mughal and Rebeck, {G. William} and LaFerla, {Frank M.} and Mattson, {Mark P.} and Nobuhisa Iwata and Saido, {Takaomi C.} and Klein, {William L.} and Duff, {Karen E.} and Aisen, {Paul S.} and Yasuji Matsuoka",

note = "Funding Information: We thank Ms. Hibiki Takenouchi, Department of Neurology, Georgetown University, for her technical assistance. Ms. Hibiki is a visiting student from Shiga University of Medical Science, Japan. We also thank Dr. Mary Ann Ottinger, University of Maryland, and Drs. Donna M. Barten and Margi Goldstein, Bristol-Myers Squibb for sharing their findings in the 3xTg-AD mouse colony maintained at their institute. Antibodies used for Abeta ELISA and Abeta immunostaining were generously provided by Dr. Noriaki Kinoshita at Immuno-Biological Laboratories. This study was supported by the National Institutes of Health (grants AG026478 and AG022455 to Y.M.), and the National Institute on Aging Intramural Research Program (MPM). ",

year = "2008",

month = jun,

day = "24",

doi = "10.1016/j.brainres.2008.03.079",

language = "English (US)",

volume = "1216",

pages = "92--103",

journal = "Brain Research",

issn = "0006-8993",

publisher = "Elsevier",

}

Hirata-Fukae, C, Li, HF, Hoe, HS, Gray, AJ, Minami, SS, Hamada, K, Niikura, T, Hua, F, Tsukagoshi-Nagai, H, Horikoshi-Sakuraba, Y, Mughal, M, Rebeck, GW, LaFerla, FM, Mattson, MP, Iwata, N, Saido, TC, Klein, WL, Duff, KE, Aisen, PS & Matsuoka, Y 2008, 'Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model', Brain research, vol. 1216, pp. 92-103. https://doi.org/10.1016/j.brainres.2008.03.079

TY - JOUR

T1 - Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model

AU - Hirata-Fukae, Chiho

AU - Li, Hui Fang

AU - Hoe, Hyang Sook

AU - Gray, Audrey J.

AU - Minami, S. Sakura

AU - Hamada, Katsuyoshi

AU - Niikura, Takako

AU - Hua, Fang

AU - Tsukagoshi-Nagai, Hiroe

AU - Horikoshi-Sakuraba, Yuko

AU - Mughal, Mohamed

AU - Rebeck, G. William

AU - LaFerla, Frank M.

AU - Mattson, Mark P.

AU - Iwata, Nobuhisa

AU - Saido, Takaomi C.

AU - Klein, William L.

AU - Duff, Karen E.

AU - Aisen, Paul S.

AU - Matsuoka, Yasuji

N1 - Funding Information: We thank Ms. Hibiki Takenouchi, Department of Neurology, Georgetown University, for her technical assistance. Ms. Hibiki is a visiting student from Shiga University of Medical Science, Japan. We also thank Dr. Mary Ann Ottinger, University of Maryland, and Drs. Donna M. Barten and Margi Goldstein, Bristol-Myers Squibb for sharing their findings in the 3xTg-AD mouse colony maintained at their institute. Antibodies used for Abeta ELISA and Abeta immunostaining were generously provided by Dr. Noriaki Kinoshita at Immuno-Biological Laboratories. This study was supported by the National Institutes of Health (grants AG026478 and AG022455 to Y.M.), and the National Institute on Aging Intramural Research Program (MPM).

PY - 2008/6/24

Y1 - 2008/6/24

N2 - Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.

AB - Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.

KW - Alzheimer's disease

KW - Amyloid beta

KW - Beta-secretase

KW - Gender difference

KW - Hyperphosphorylation

KW - Neprilysin

KW - Oligomer

KW - Tau

KW - Transgenic mice

UR - http://www.scopus.com/inward/record.url?scp=44949210283&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44949210283&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2008.03.079

DO - 10.1016/j.brainres.2008.03.079

M3 - Article

C2 - 18486110

AN - SCOPUS:44949210283

SN - 0006-8993

VL - 1216

SP - 92

EP - 103

JO - Brain Research

JF - Brain Research

ER -

Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model

Abstract

Keywords

ASJC Scopus subject areas

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