Abstract
Oxidative stress was implicated in the functional impairment of the frontal cortex observed in early Alzheimer’s disease (AD). To elucidate this role in an animal AD model, we assessed cognitive function of 4-month-old five familial AD (5XFAD) transgenic (Tg) mice using a learning strategy-switching task requiring recruitment of the frontal cortex and measuring levels of 4-hydroxy-2-trans-nonenal (4-HNE), a marker of oxidative stress, in their frontal cortex. Mice were sequentially trained in cued/response and place/spatial versions of the water maze task for four days each. 5XFAD and non-Tg mice exhibited equal performance in cued/response training. However, 5XFAD mice used spatial search strategy less than non-Tg mice in the spatial/place training. Immunoblot and immunofluorescence staining showed that 4-HNE levels increased in the frontal cortex, but not in the hippocampus and striatum, of 5XFAD mice compared to those in non-Tg mice. We report early cognitive deficits related to the frontal cortex and the frontal cortex’s oxidative damage in 4-month-old 5XFAD mice. These results suggest that 4-month-old 5XFAD mice be a useful animal model for the early diagnosis and management of AD.
Highlights
Oxidative stress was reported to play a crucial role in the pathogenesis of neurodegenerative disorders, including Alzheimer’s disease (AD) [1,2,3], where it features prominently in early AD and mild cognitive impairment (MCI) [4,5]
Oxidative damage is more pronounced in the frontal cortex than in other cortices in the AD brain [9,10]
In the AD brain, oxidative stress induced by accumulation of Aβ peptides leads to inflammation and mediates neurotoxic effects of protein aggregates, including ceramide, resulting in functional and mediates neurotoxic effects of protein aggregates, including ceramide, resulting in functional impairments [25]
Summary
Oxidative stress was reported to play a crucial role in the pathogenesis of neurodegenerative disorders, including Alzheimer’s disease (AD) [1,2,3], where it features prominently in early AD and mild cognitive impairment (MCI) [4,5]. Increased 4-hydroxy-2-trans-nonenal (4-HNE)-modified protein has been demonstrated in MCI, as well as in both early and late-stage AD [6,7,8] These studies indicate that cognitive decline in AD is more pronounced with more severe oxidative damage, as indexed by protein-bound 4-HNE [7]. A study linking early cognitive impairment to the frontal cortex in 5XFAD mice examined the cognitive status of 2-, 4-, and 6-month-old. Biomedicines 2020, 8, 326 a sensitive marker of frontal cortex status It reported that cognitive deficits, heavy gliosis, and emerging amyloid plaques were apparent in 4-month-old 5XFAD mice [12]. Their results suggest that 5XFAD mice of that age should be useful when studying early AD and assessing frontal brain function in transgenic AD mice. Recent studies have reported that oxidative damage is observed in the frontal cortex in early AD [1,2,3], and 4-month-old
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