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Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline
| Content Provider | Semantic Scholar |
|---|---|
| Author | Macklin, Lauren N. Griffith, Chelsea M. Rose, Gregory M. Patrylo, Peter R. |
| Copyright Year | 2017 |
| Abstract | &NA; Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta‐amyloid (A&bgr;) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggests that both type 1 and type 2 diabetes are risk factors for AD‐related dementia and several clinical studies have demonstrated that AD patients show alterations in peripheral glucose regulation characterized by insulin resistance (hyperinsulinemia) or hypoinsulinemia. Whether animal models of AD exhibit a pre‐diabetic phenotype without additional dietary or experimental manipulation is unclear however, with contradictory data available. Further, most studies have not examined the time course of potential pre‐diabetic changes relative to AD pathogenesis and cognitive decline. Thus, in this study we tested the hypothesis that a pre‐diabetic phenotype (peripheral metabolic dysregulation) exists in the APP/PS1 transgenic model of AD under normal conditions and precedes AD‐related pathology. Specifically, we examined glucose tolerance in male APP/PS1 mice on a C57BL/6J congenic background at 2, 4–6 and 8–9 months of age by assessing fasting glucose levels, glucose tolerance, plasma insulin levels and insulin sensitivity as well as the development of pathological characteristics of AD and verified that our APP/PS1 mice develop cognitive impairment. Here we show that APP/PS1 mice, compared to wild‐type controls, exhibit a significant impairment in glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT) and a trend for increased fasting plasma insulin concentrations as early as 2 months of age, while extracellular A&bgr;1–42 deposition occurs later and cognitive decline exists at 8–9 months of age. Moreover, APP/PS1 mice did not respond as well to exogenous insulin as the wild‐type controls during an intraperitoneal insulin tolerance test (ipITT). Taken together, these data reveal that male APP/PS1 mice on a C57BL/6J congenic background exhibit a pre‐diabetic phenotype prior to the development of AD‐like pathology and that this metabolic deficit persists when they exhibit neuropathology and cognitive decline. This raises the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis. HighlightsThe APP/PS1 mouse is an animal model of Alzheimer's disease.A&bgr; plaques are seen at 6–7 months in APP/PS1 mice but not at 2 months.Spatial learning and memory is impaired in APP/PS1 mice at 8–9 months.In contrast, peripheral glucose regulation is altered by 2 months in APP/PS1 mice.Thus, a pre‐diabetic phenotype precedes classical AD‐related pathology. |
| Starting Page | 9 |
| Ending Page | 18 |
| Page Count | 10 |
| File Format | PDF HTM / HTML |
| DOI | 10.1016/j.exger.2016.12.019 |
| PubMed reference number | 28025127 |
| Journal | Medline |
| Volume Number | 88 |
| Alternate Webpage(s) | https://api.elsevier.com/content/article/pii/S0531556516304107 |
| Alternate Webpage(s) | https://www.sciencedirect.com/science/article/pii/S0531556516304107?dgcid=api_sd_search-api-endpoint |
| Alternate Webpage(s) | https://doi.org/10.1016/j.exger.2016.12.019 |
| Journal | Experimental Gerontology |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
