Heart and vascular responses across the lifespan in Ts65Dn mice, a model of Down syndrome

摘要

ABSTRACT Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability and results from triplication of chromosome 21 genes. Persons with Ds demonstrate cognitive deficits and early development of Alzheimer’s disease (AD). A well-characterized mouse model of Ds is the Ts65Dn mouse. This model has neuroanatomical changes indicative of AD by 6 months of age and worsening behavioral deficits between 6 and 11 months. In addition to cognitive abnormalities in Ds, co-morbidities include cardiovascular alterations that are mediated by the autonomic nervous system. Specific Aim 1 of the parent award will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. Autonomic tone will be operationally defined and measured by heart rate variability. This supplemental application plans to examine behavioral measures in these same mice. Barnes maze, novel object recognition, open field, and elevated plus maze will be performed prior to the cardiovascular experiments for each age group. These proposed investigations address the NICHD topic of interest “The significantly increased risk of Alzheimer’s disease in adults with Down syndrome” listed in NOT-AG-20-3. Ts65Dn has cognitive deficits in early development and then some measures, such as spatial learning and memory, worsen in later months. These worsening behavioral measures are considered to represent the presentation of behavior and outwards AD or other dementia in Ts65Dn. In this supplement, we plan to correlate behavioral tests with heart rate variability measures. Lower high frequency heart rate variability is indicative of lower parasympathetic tone. In some human studies, lower high frequency heart rate variability (lower parasympathetic tone) corresponds to cognitive impairment. We have previously published that Ts65Dn also has lower high frequency heart rate variability (lower parasympathetic tone) at 9 months of age. Since behavioral changes indicative of AD present between 6- 11 months in Ts65Dn, we hypothesize that heart rate variability changes will correlate, or even precede the behavior. This supplement plans to investigate if heart rate variability could be used as a non-invasive marker to determine the prodromal phase of AD.