Genotype and Sex Differences in Longevity in Transgenic Mouse Models of Alzheimer’s Disease

Brown, Richard E.; Shin, Sooyoun; Woodland, Nicole; Rae, Eric A.

doi:10.1016/b978-0-12-811353-0.00042-7

Cited by 3 publications

(6 citation statements)

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“…Noteworthy, we have recently reported survival bias and crosstalk between chronological and behavioral age in an APPswe model, where age-and genotype-sensitivity tests defined behavioral signatures in middle-aged, old, and long-lived mice with normal and AD-associated aging [51]. Therefore, the present work provides further evidence on sex and genotype-dependent differences in life expectancy and supports the key role of frailty and compensatory mechanisms as previously reported by our and other laboratories using different models of AD [29,[49][50][51][52].…”

Section: Discussionsupporting

confidence: 89%

Impact of Behavioral Assessment and Re-Test as Functional Trainings That Modify Survival, Anxiety and Functional Profile (Physical Endurance and Motor Learning) of Old Male and Female 3xTg-AD Mice and NTg Mice with Normal Aging

Castillo-Mariqueo

2022

Biomedicines

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Longitudinal approaches for disease-monitoring in old animals face survival and frailty limitations, but also assessment and re-test bias on genotype and sex effects. The present work investigated these effects on 56 variables for behavior, functional profile, and biological status of male and female 3xTg-AD mice and NTg counterparts using two designs: (1) a longitudinal design: naïve 12-month-old mice re-tested four months later; and (2) a cross-sectional design: naïve 16-month-old mice compared to those re-tested. The results confirmed the impact as (1) improvement of survival (NTg rested females), variability of gait (3xTg-AD 16-month-old re-tested and naïve females), physical endurance (3xTg-AD re-tested females), motor learning (3xTg-AD and NTg 16-month-old re-tested females), and geotaxis (3xTg-AD naïve 16-month-old males); but (2) worse anxiety (3xTg-AD 16-month-old re-tested males), HPA axis (3xTg-AD 16-month-old re-tested and naïve females) and sarcopenia (3xTg-AD 16-month-old naïve females). Males showed more functional correlations than females. The functional profile, biological status, and their correlation are discussed as relevant elements for AD-pathology. Therefore, repetition of behavioral batteries could be considered training by itself, with some variables sensitive to genotype, sex, and re-test. In the AD-genotype, females achieved the best performance in physical endurance and motor learning, while males showed a deterioration in most studied variables.

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Section: Discussionsupporting

confidence: 89%

Impact of Behavioral Assessment and Re-Test as Functional Trainings That Modify Survival, Anxiety and Functional Profile (Physical Endurance and Motor Learning) of Old Male and Female 3xTg-AD Mice and NTg Mice with Normal Aging

Castillo-Mariqueo

2022

Biomedicines

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“…There are considerable genotype and sex differences in life expectancy among inbred mouse strains and among the different mouse models of AD (Rae and Brown, 2015 ; Brown et al, 2018 ). Although many AD mouse models have shorter lifespans than their wild-type (WT) controls, this is not observed in all models (Rae and Brown, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…There are also sex differences in the lifespan of some AD mouse models, including 3xTg-AD mice, in which males have a shorter lifespan than females (Westmark et al, 2010 ; Rae and Brown, 2015 ). In some models, however, males have longer lifespans than females (Pugh et al, 2007 ), or there is no sex difference (Rae and Brown, 2015 ; Brown et al, 2018 ). This makes it difficult to compare the lifespan and interventional data across different AD mouse models and between the sexes, as well as the translation of data from animal studies to the clinic.…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Kane

Shin

Wong

et al. 2018

Front. Aging Neurosci.

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Mouse models of Alzheimer’s disease (AD) exhibit marked differences in life expectancy depending on their genotype and sex. The assessment of frailty could provide a measure of healthspan to facilitate comparisons between different AD models. We used a validated mouse frailty index (FI) assessment tool to explore genotype and sex differences in lifespan and healthspan of 3xTg-AD mice and their B6129F2 wild-type (WT) controls. This tool is based on an approach commonly used in people and quantifies frailty by counting the accumulation of age-related health deficits. The number of deficits in an individual divided by the total number measured yields an FI score theoretically between 0 and 1, with higher scores denoting more frailty. Male 3xTg-AD mice aged 300–600 days had higher FI scores (Mean FI = 0.21 ± 0.03) than either male WT (Mean FI = 0.15 ± 0.01) or female 3xTg-AD mice (Mean FI = 0.10 ± 0.01), and the elevated frailty scores were accompanied by parallel increases in mortality. Frailty increased exponentially with age, and higher rates of deficit accumulation elevated mortality risk in all groups of mice. When mice were stratified by FI score, frailty predicted mortality, at least in females. Therefore, the mouse clinical FI provides a valuable tool for evaluating healthspan in mouse models of AD with different lifespans.

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“…A study of 1,028 deceased subjects reported that while the age of onset to dementia did not differ on the basis of gender, females, once they were diagnosed, were more likely to proceed to a severe pathological phenotype with a greater severity of neurofibrillary changes and changes in brain weight as compared to males (Filon et al., ). Similar controversies exist preclinically with reported sex differences in rat and mouse models of learning and memory (Jonasson, ), and in transgenic mice (Rae & Brown, ), where reports of females outliving males among 3×Tg‐AD and Tg2576 mice have not been confirmed in other transgenic AD models (Brown et al., ). These conflicting data will no doubt be resolved as the result of the NIH initiative to “monitor compliance of sex and gender inclusion in preclinical research funded by the agency” (Clayton & Collins, ) such that the contributions of sex can be considered alongside genotype in considering the results generated from animal models of AD.…”

Section: Gender Differences In Animal Models Of Admentioning

confidence: 66%

“…Current Protocols in Pharmacology outliving males among 3×Tg-AD and Tg2576 mice have not been confirmed in other transgenic AD models (Brown et al, 2018). These conflicting data will no doubt be resolved as the result of the NIH initiative to "monitor compliance of sex and gender inclusion in preclinical research funded by the agency" (Clayton & Collins, 2014) such that the contributions of sex can be considered alongside genotype in considering the results generated from animal models of AD.…”

Section: Of 28mentioning

confidence: 99%

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

Mullane

Williams

2019

CP Pharmacology

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The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40‐year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease‐associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs—including their bioavailability and toxicity—the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged‐related dementias. © 2019 by John Wiley & Sons, Inc.

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Genotype and Sex Differences in Longevity in Transgenic Mouse Models of Alzheimer’s Disease

Cited by 3 publications

References 161 publications

Impact of Behavioral Assessment and Re-Test as Functional Trainings That Modify Survival, Anxiety and Functional Profile (Physical Endurance and Motor Learning) of Old Male and Female 3xTg-AD Mice and NTg Mice with Normal Aging

Impact of Behavioral Assessment and Re-Test as Functional Trainings That Modify Survival, Anxiety and Functional Profile (Physical Endurance and Motor Learning) of Old Male and Female 3xTg-AD Mice and NTg Mice with Normal Aging

Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

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