Klotho gene was originally recognized as a putative aging-suppressor and its prominent age-regulating effects are mostly attributed to the modulation of mineral homeostasis in the kidney. However, recent studies link alterations in hippocampal Klotho expression with cognitive impairment and neurodegenerative diseases. This suggests that hippocampal neurons require Klotho for health and proper functionality. Klotho protects against neuronal dysfunction and regulates several intracellular signaling pathways including oxidative stress response, inflammation, DNA damage, autophagy, endoplasmic reticulum stress response, and multiple types of cell death. Specifically, this chapter covers the current knowledge as to how Klotho protein affects the hippocampal neuronal cells, with special attention paid to underlying molecular mechanisms, and thus influences hippocampal development, hippocampal-dependent cognition, behavior, and motor skills as well as mediates neurodegenerative processes.
Keywords: Autophagy; Cell death; DNA damage; ER stress; Hippocampus; Inflammation; Klotho; Neurons; Oxidative stress.
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