Characterization of Murine Models of Calcium Dysregulation and Metabolic Dysfunction: Implications for Cognition and Neuroinflammation

Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial conditions in which alterations in different cellular and systemic processes may converge to impair neuronal function and cognition. In this work, we sought to explore the contribution of distinct mechanisms associated with neuronal dysfunction, focusing on intracellular calcium signaling, metabolic dysfunction, and neuroinflammation as distinct but potentially convergent mechanisms associated with cognitive impairment. Three murine models were studied: Ob/Ob mice (leptin mutation) and SAKO and SDKO mice (RyR2 mutations). Cognitive function was assessed using the Barnes Maze, while hippocampal neurogenesis and neuroinflammation were evaluated by immunoassays and RT-qPCR. It was observed that SAKO and Ob/Ob mice showed significant cognitive deficits (p=0.0234; p=0.0034) and reduced neurogenesis (p=0.0007; p=0.0109). A non-significant trend toward increased expression of the pro-inflammatory mediators IL-6 and Tyrobp was also observed (p=0.2858; p=0.1905). These findings indicate that alterations in distinct biological processes, including intracellular calcium signaling and metabolic dysfunction, are associated with convergent changes in cognition, and hippocampal neurogenesis. Together, our results support the relevance of investigating multiple interacting cellular and systemic mechanisms to better understand the multifactorial nature of neurodegenerative diseases such as AD.