Targeting protein misfolding in Alzheimer's disease: The emerging role of molecular chaperones

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline and the accumulation of misfolded proteins, including amyloid-beta and hyperphosphorylated tau, which impair neuronal function and promote cell death. These misfolded proteins disrupt proteostasis by forming toxic aggregates that exacerbate disease progression. Molecular chaperones, such as heat shock proteins, actively maintain protein homeostasis by assisting in proper folding, preventing aggregation, and promoting the clearance of misfolded proteins. Dysfunction in chaperone systems contributes to the pathogenesis of AD, positioning them as promising therapeutic targets. Recent research has explored chaperone-based interventions, including small molecules, gene therapies, and autophagy and proteasomal degradation modulators, to restore protein balance. Advances in high-throughput screening and omics technologies have accelerated the identification of potential chaperone modulators. Despite these developments, the complexity of AD and the shortcomings of existing disease models make it difficult to translate preclinical results into successful clinical treatments. This review critically examines the role of protein misfolding and chaperone dysfunction in AD, evaluates emerging therapeutic strategies, and highlights current clinical trials, aiming to bridge molecular mechanisms with translational opportunities in the pursuit of novel AD treatments.