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) |
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Pages (from-to) | 98-110 |
Number of pages | 13 |
Journal | Neurobiology of Aging |
Volume | 123 |
DOIs | |
State | Published - Mar 2023 |
Funding
This work was supported by R37AG008796 , RF1AG017139 , R01NS113804 , P30CA060553 , 5P30AG013854-25, R01AG061787 and R01AG078796 . 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.
Keywords
- 6E10
- Learning index
- Neuroinflammation
- Proteomics
- TREM2
- Watermaze
- pTau
ASJC Scopus subject areas
- Clinical Neurology
- Geriatrics and Gerontology
- Aging
- General Neuroscience
- Developmental Biology