α-Klotho as a central integrative signalling hub in cognitive function and neuroprotection in neurodegenerative diseases.

α-Klotho, a transmembrane protein predominantly expressed in the kidney and brain, has garnered significant attention for its anti-ageing and neuroprotective properties. Beyond its systemic role in mineral metabolism and oxidative stress regulation, emerging evidence highlights its critical involvement in maintaining cognitive function and protecting against neurodegenerative processes. This review explores the multifaceted role of α-Klotho in the central nervous system, emphasizing its physiological functions, underlying molecular mechanisms, and therapeutic potential. α-Klotho exerts neuroprotective effects by modulating calcium and phosphate homeostasis, attenuating oxidative stress, and suppressing neuroinflammation. Additionally, it regulates signalling pathways such as IGF-1, Wnt/β-catenin, and Nrf2, which are essential for neuronal survival and synaptic plasticity. Reduced α-Klotho expression has been linked to cognitive impairment, Alzheimer's disease, Parkinson's disease, and other age-related neurodegenerative disorders. Preclinical studies demonstrate that enhancing α-Klotho expression or administering a recombinant protein improves learning, memory, and neuronal resilience, positioning α-Klotho as a promising therapeutic target. However, challenges such as limited blood-brain barrier penetration, stability of recombinant forms, and incomplete mechanistic understanding hinder clinical translation. Overall, α-Klotho stands as a novel biomarker and a promising intervention strategy for mitigating neurodegeneration and promoting healthy brain ageing.