Survival Curves and Behavioral Profiles of Female 3xTg-AD Mice Surviving to 18-Months of Age as Compared to Mice with Normal Aging

Abstract

New evidence reveals a high degree of heterogeneity in Alzheimer's disease (AD) clinical and temporal patterns, supporting the existence of several subgroups of patients. Prognosticators of end-of-life dementia specific to elderly patients are necessary to address this heterogeneity. Among 3xTg-AD mice, a widely-used model for AD, a very small number of animals overcome advanced neuropathological stages of disease beyond 18 months of age. They are usually females, which reach longevity in spite of worse neuropathological status as compared to males (the morbidity/mortality paradox). We posit that 3xTg-AD long-term survivors could serve to model end-of-life dementia but also aware about the mortality selection bias. In the present study, we performed behavioral and functional phenotype in long-term survivors, 18-month-old female 3xTg-AD mice and age-matched wildtype undergoing normal aging. Animals were followed up until natural death to correlate survival with phenotype assessments. Strong similarity of their behavioral profiles in all the variables analyzed (e.g. reflexes, sensorimotor functions, locomotion, exploration, emotionality, and anxiety-like behaviors) was found, with the exception of memory impairment, which was a salient trait in old 3xTg-AD survivors. The two groups showed similar mean life expectancy and had behavioral correlates among lifespan, neophobia and long-term memory in common, with some distinctions in 3xTg-AD, supporting recent studies in end-of-life patients. In spite of the small sample size, this brief report presents an interesting scenario to further study heterogeneity and survival in Alzheimer's disease. 3xTg-AD survivors may be a model to gain insight into the frailty/survival paradigm in normal and pathological aging.

Keywords: Alzheimer’s disease; animal model; behavioral correlates; end-of-life; frailty; heterogeneity; survivorship.

Fig.1

Similar exploratory activity patterns and total counts exhibited in the anxiogenic open-field test in 18-month-old female 3xTg-AD mice as compared to sex- and age-matched NTg mice with normal aging. Interestingly, horizontal activity (number of crossings) shown in the first minute of the test, a variable that measures the level of neophobia to this new environment, correlated (© positive Pearson’s correlation, p < 0.05) with lifespan of NTg and 3xTg-AD mice (see Fig. 4B and 4J).

Fig.2

Salient learning and memory deficits in three paradigms of the Morris water maze in 18-month-old female 3xTg-AD mice surviving to advanced stages of disease as compared to age-matched NTg counterparts. A) The cue and place tasks showed similar acquisition curves over days, but genotype differences could be found when the platform was hidden and located in a reversed position. The new task was more difficult for animals remembering the prior location, so it took them more time to find the new position. B) Detailed analysis of short- and long-term memory assessed in the place tasks evidenced that cognitive impairment was the salient trait for distinguishing the genotypes. C) Memory, assessed in the Removal, showed lack of preference for the trained quadrant in both groups pf mice, with a slightly worse performance in the 3xTg-AD mice. Student’s t-test, ^*p < 0.05, ^**p < 0.01 versus NTg mice. Paired t-test ^# p < 0.05, ^# # # p < 0.001 PT1 versus Cue2. (©) Pearson’s correlations between behavioral variables and lifespan: ^•positive, °negative, p < 0.01.

Fig.3

Difference in the survival curves of 18-month-old female 3xTg-AD mice and age-matched NTg counterparts was found in spite of similar mean life expectancies. Kaplan-Meyer test, ^* p < 0.05.

Fig.4

In six 18-month-old female 3xTg-AD mice and five age-matched NTg counterparts, Pearson’s correlations between lifespan and behaviors were studied. Correlations (p < 0.01) found between lifespan and long-term memory in old 3xTg-AD mice (n = 6), and between lifespan and sensorimotor abilities in old NTg mice (n = 5). Correlation p < 0.05 was also found between lifespan and neophobia as assessed in the corner- and open-field tests (in the 3xTg-AD mice) but also in the T-maze (all sample, n = 11). Besides, long-term memory correlates showed a good consistency, since they also showed correlations p < 0.05 with lifespan in the old NTg mice (n = 5) and when the whole sample was analyzed (n = 11). Short-term memory was found to be correlated with lifespan in the sample of NTg mice (n = 5). Further studies in a larger sample size are needed. (©) Pearson’s correlations between behavioral variables and lifespan: ^•positive, °negative, p < 0.01.