The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease

Birsu Bac; Cheima Hicheri; Craig Weiss; Amelia Buell; Natalia Vilcek; Claudia Spaeni; Changiz Geula; Jeffrey N. Savas; John F. Disterhoft

doi:10.1016/j.neurobiolaging.2022.12.015

The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease

Birsu Bac, Cheima Hicheri, Craig Weiss, Amelia Buell, Natalia Vilcek, Claudia Spaeni, Changiz Geula, Jeffrey N. Savas, John F. Disterhoft^*

^*Corresponding author for this work

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

1 Scopus citations

Abstract

Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.

Original language	English (US)
Pages (from-to)	98-110
Number of pages	13
Journal	Neurobiology of Aging
Volume	123
DOIs	https://doi.org/10.1016/j.neurobiolaging.2022.12.015
State	Published - Mar 2023

Keywords

6E10
Learning index
Neuroinflammation
Proteomics
TREM2
Watermaze
pTau

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Aging
Neuroscience(all)
Developmental Biology

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10.1016/j.neurobiolaging.2022.12.015

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title = "The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease",

abstract = "Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.",

keywords = "6E10, Learning index, Neuroinflammation, Proteomics, TREM2, Watermaze, pTau",

author = "Birsu Bac and Cheima Hicheri and Craig Weiss and Amelia Buell and Natalia Vilcek and Claudia Spaeni and Changiz Geula and Savas, {Jeffrey N.} and Disterhoft, {John F.}",

note = "Funding Information: This work was supported by R37AG008796 , RF1AG017139 , R01NS113804 , P30CA060553 , 5P30AG013854-25, R01AG061787 and R01AG078796 . Funding Information: Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center . Behavioral assays were performed at the Northwestern University Behavioral Phenotyping Core Facility. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2023",

month = mar,

doi = "10.1016/j.neurobiolaging.2022.12.015",

language = "English (US)",

volume = "123",

pages = "98--110",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

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T1 - The TgF344-AD rat

T2 - behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease

AU - Bac, Birsu

AU - Hicheri, Cheima

AU - Weiss, Craig

AU - Buell, Amelia

AU - Vilcek, Natalia

AU - Spaeni, Claudia

AU - Geula, Changiz

AU - Savas, Jeffrey N.

AU - Disterhoft, John F.

N1 - Funding Information: This work was supported by R37AG008796 , RF1AG017139 , R01NS113804 , P30CA060553 , 5P30AG013854-25, R01AG061787 and R01AG078796 . Funding Information: Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center . Behavioral assays were performed at the Northwestern University Behavioral Phenotyping Core Facility. Publisher Copyright: © 2022 The Author(s)

PY - 2023/3

Y1 - 2023/3

N2 - Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.

AB - Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.

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KW - Neuroinflammation

KW - Proteomics

KW - TREM2

KW - Watermaze

KW - pTau

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SN - 0197-4580

VL - 123

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EP - 110

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease

Abstract

Keywords

ASJC Scopus subject areas

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