Sex differences in the IntelliCage and the Morris water maze in the APP/PS1 mouse model of amyloidosis

Mifflin, Marc A.; Winslow, Wendy; Surendra, Likith; Tallino, Savannah; Vural, Austin S.; Velázquez, Ramón

doi:10.1016/j.neurobiolaging.2021.01.018

Cited by 49 publications

(33 citation statements)

References 52 publications

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“…Studies in 5xFAD mice have found that female mice display greater molecular pathology ( Sadleir et al, 2015 ; Bundy et al, 2019 ), higher levels of cerebral Aβ42 ( Sadleir et al, 2015 ), and a greater Aβ plaque burden than male mice ( Bhattacharya et al, 2014 ; Reid and Darvesh, 2015 ). Similar sex-related differences in pathology have also been observed in other transgenic models of AD, including the APP/PS1 ( Li et al, 2016 ; Mifflin et al, 2021 ) and 3xTg-AD ( Carroll et al, 2010 ; Yang et al, 2018 ) models.…”

Section: Discussionsupporting

confidence: 69%

Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

et al. 2021

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Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer’s disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß-amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer’s disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.

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Section: Discussionsupporting

confidence: 69%

Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

et al. 2021

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“…Mice were group housed (4 to 5 mice per cage) prior to being introduced into the IntelliCage. At 7-9 months of age, prior to IntelliCage testing, a radiofrequency identification transponder chip (RFID; Standard Microchip T-VA, DataMars, Switzerland and Troven, USA) was subcutaneously implanted into the dorso-cervical region under isoflurane inhalation anesthesia as previously described (Mifflin et al, 2021). The RFID chip allows for the identification of a mouse when it enters a corner of the IntelliCage system.…”

Section: Animalsmentioning

confidence: 99%

“…The IntelliCage was used to evaluate water drinking, exploratory behavior, spatial learning, reference memory, behavioral flexibility, attention, and contextual memory (Masuda et al, 2016(Masuda et al, , 2018Kiryk et al, 2020;Mifflin et al, 2021). The testing apparatus (39 cm × 58 cm × 21 cm) contains four corner chambers accessible through an antenna-equipped open tunnel.…”

Section: Automated Intellicage Testingmentioning

confidence: 99%

“…In 2000, Dr. Hans-Peter Lipp developed the IntelliCage, which helps overcome these factors by allowing rodents to be tested in their natural social environment with minimal human intervention (Dell'Omo et al, 2000;Lipp, 2005;Lipp et al, 2005). The IntelliCage is a fully-automated system allowing animals to engage in a wide variety of experimental tasks, using access to water as their incentive to participate, and has since been used in over 150 studies (Lipp et al, 2005;Lipp, 2005;Masuda et al, 2018;Kiryk et al, 2020;Mifflin et al, 2021). Animals can be assessed for exploratory behavior, water consumption patterns, spatial learning, behavioral flexibility, attention, impulsivity, and working and contextual memory within a single cage.…”

Section: Introductionmentioning

confidence: 99%

“…Animals can be assessed for exploratory behavior, water consumption patterns, spatial learning, behavioral flexibility, attention, impulsivity, and working and contextual memory within a single cage. While APP/KI and APP/PS1 mouse models of amyloidosis have been tested in the IntelliCage, to date, the 3xTg-AD model has not been evaluated in this automated behavioral phenotyping apparatus (Ryan et al, 2013;Lee et al, 2015;Masuda et al, 2016;Mifflin et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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IntelliCage Automated Behavioral Phenotyping Reveals Behavior Deficits in the 3xTg-AD Mouse Model of Alzheimer’s Disease Associated With Brain Weight

Winslow

McDonough

Tallino

et al. 2021

Front. Aging Neurosci.

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Transgenic rodent models of Alzheimer’s disease (AD) were designed to study mechanisms of pathogenesis and connect these mechanisms with cognitive decline. Measurements of cognition in rodents can be confounded, however, by human handling and interaction; the IntelliCage was created to circumvent these issues while measuring various facets of cognition in a social environment with water consumption as the primary motivator for task completion. Here, for the first time, we examined the behavioral performance of 3xTg-AD mice in the IntelliCage. Seven- to 9-month-old female 3xTg-AD and non-transgenic (NonTg) mice were tested for 29 days in the IntelliCage to measure prefrontal cortical and hippocampal function. We found that a higher percentage of NonTg mice (86.96%) were able to successfully complete the training (adaptation) phases compared to their 3xTg-AD (57.14%) counterparts. Furthermore, the 3xTg-AD mice showed impairments in attention and working memory. Interestingly, we found that differences in body and brain weight between NonTg and 3xTg-AD mice were associated with whether mice were able to complete the IntelliCage tasks. 3xTg-AD mice that completed IntelliCage tasks had lower cortical insoluble amyloid-β40 fractions than their 3xTg-AD counterparts who failed to complete the tasks. Collectively, these results demonstrate deficits in cognition in the 3xTg-AD mouse and inform scientists of important factors to consider when testing this transgenic model in the IntelliCage.

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Inflammation and the pathological progression of Alzheimer’s disease are associated with low circulating choline levels

Judd,

Jasbi,

Winslow

et al. 2023

Acta Neuropathol

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Deficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer’s disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch−) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice, two rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNFα was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNFα correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNFα. Choline and ACh levels were negatively correlated with neuritic plaque load, Braak stage, and TNFα, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch− diet increased amyloid-β levels and tau phosphorylation in cortical tissue, and TNFα in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+ diet increased choline and ACh while reducing amyloid-β and TNFα levels in brains of APP/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease.

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Sex differences in the IntelliCage and the Morris water maze in the APP/PS1 mouse model of amyloidosis

Cited by 49 publications

References 52 publications

Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

IntelliCage Automated Behavioral Phenotyping Reveals Behavior Deficits in the 3xTg-AD Mouse Model of Alzheimer’s Disease Associated With Brain Weight

Inflammation and the pathological progression of Alzheimer’s disease are associated with low circulating choline levels

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