Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease. (19th August 2019)

• Record Type: Journal Article
• Authors: O'Connell, Kristen M. S.; Ouellette, Andrew R.; Neuner, Sarah M.; Dunn, Amy R.; Kaczorowski, Catherine C.
• Is Part Of: Genes, brain, and behavior. Volume 18:Number 8(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-08-19
• Subjects: alzheimer's disease -- balance -- coordination -- dementia -- genetics -- muscle -- noncognitive -- preclinical AD -- sensorimotor function; Behavior genetics -- Periodicals; Neurogenetics -- Periodicals; 616.8
• DOI: 10.1111/gbb.12603
• Languages: English
• ISSNs: 1601-1848

Abstract

Abstract: Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD‐BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD‐BXDs and the relationship to cognitive decline in these mice. We found that age‐ and AD‐related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD‐BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging‐ and AD‐related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD‐related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease. Abstract : Sensorimotor deficits in Alzheimer's disease are distinct from AD‐related cognitive decline or normal age‐related decline.