“…Our data in the 5xFAD model of AD shows that, in the early-mid stages of cognitive decline at 6 months of age, there was an evident decrease in body weight that was more prominent in females, as both Tg 5xFAD/and Tg 5xFAD/5xFAD showed this feature. Our results are in accordance with previous studies in 5xFAD mice of 6, 7.5, 9, and 12 months of age, showing weight loss in female full transgenic mice [44,45]. However, we also observed male weight loss in Tg 5xFAD/5xFAD males, but not in the Tg 5xFAD/mice.…”
Section: Body Weight Deficit In 5xfad Micesupporting
confidence: 93%
“…The exact causes for weight loss are, however, still under discussion and seem to be fairly related to decreased food intake and disruptions in the sleep pattern [48,49]. In our study, we found that body weight decrease was significantly associated with decreased food intake, more prominently during the active phase (night), in accordance with previous studies in the same mouse model of AD [45]. It has also been reported that behavioral factors such as anhedonia and depression in AD patients are correlated to decreased food intake and weight loss [51].…”
Section: Body Weight Deficit In 5xfad Micesupporting
confidence: 91%
“…Instead, we also observed a decreased EE in full 5xFAD transgenic mice, more preeminently in female mice during active phase (night), in accordance with the food intake pattern of activity we observed. These results show that weight loss in 5xFAD mice at 6 months of age are not related to hyperactivity nor energy expenditure, as other studies have also shown decreased motility and locomotor activity in male and female 5xFAD mice, which were associated with increased frailty [45,56]. The main differences between energy metabolism in 5xFAD and other mouse models of AD reside in either mutation leading to Tau hyperphosphorylation or behavioral traits, which may be a cause for observed hypermetabolism [55].…”
Section: Alterations In Food Intake and Energy Expenditure In 5xfad Micesupporting
confidence: 59%
“…Studies in different mouse models of AD such as the 3xTg have shown differences in body weight at early age, showing decreased body weight in male mice but, conversely, increased in female mice when other studies showed decreased body weight in both male and female 3xTG mice at 3 months of age [13,46]. According to previous studies in mouse models of AD, this body weight deficit seems to be mainly associated with white fat mass loss [13,43,45]. Weight loss is usually observed in AD patients, and BMI is also a marker for AD cognitive decline as changes in stages of AD are related to cumulative weight loss [47][48][49].…”
Section: Body Weight Deficit In 5xfad Micementioning
Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
“…Our data in the 5xFAD model of AD shows that, in the early-mid stages of cognitive decline at 6 months of age, there was an evident decrease in body weight that was more prominent in females, as both Tg 5xFAD/and Tg 5xFAD/5xFAD showed this feature. Our results are in accordance with previous studies in 5xFAD mice of 6, 7.5, 9, and 12 months of age, showing weight loss in female full transgenic mice [44,45]. However, we also observed male weight loss in Tg 5xFAD/5xFAD males, but not in the Tg 5xFAD/mice.…”
Section: Body Weight Deficit In 5xfad Micesupporting
confidence: 93%
“…The exact causes for weight loss are, however, still under discussion and seem to be fairly related to decreased food intake and disruptions in the sleep pattern [48,49]. In our study, we found that body weight decrease was significantly associated with decreased food intake, more prominently during the active phase (night), in accordance with previous studies in the same mouse model of AD [45]. It has also been reported that behavioral factors such as anhedonia and depression in AD patients are correlated to decreased food intake and weight loss [51].…”
Section: Body Weight Deficit In 5xfad Micesupporting
confidence: 91%
“…Instead, we also observed a decreased EE in full 5xFAD transgenic mice, more preeminently in female mice during active phase (night), in accordance with the food intake pattern of activity we observed. These results show that weight loss in 5xFAD mice at 6 months of age are not related to hyperactivity nor energy expenditure, as other studies have also shown decreased motility and locomotor activity in male and female 5xFAD mice, which were associated with increased frailty [45,56]. The main differences between energy metabolism in 5xFAD and other mouse models of AD reside in either mutation leading to Tau hyperphosphorylation or behavioral traits, which may be a cause for observed hypermetabolism [55].…”
Section: Alterations In Food Intake and Energy Expenditure In 5xfad Micesupporting
confidence: 59%
“…Studies in different mouse models of AD such as the 3xTg have shown differences in body weight at early age, showing decreased body weight in male mice but, conversely, increased in female mice when other studies showed decreased body weight in both male and female 3xTG mice at 3 months of age [13,46]. According to previous studies in mouse models of AD, this body weight deficit seems to be mainly associated with white fat mass loss [13,43,45]. Weight loss is usually observed in AD patients, and BMI is also a marker for AD cognitive decline as changes in stages of AD are related to cumulative weight loss [47][48][49].…”
Section: Body Weight Deficit In 5xfad Micementioning
Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
A major obstacle in Alzheimer’s disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized Aβ sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of Aβ plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.
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