Abstract
Alzheimer’s disease (AD) is a widespread neurodegenerative disorder
characterized by progressive memory and cognitive decline, posing a formidable
public health challenge. This review explores the intricate interplay between
two pivotal players in AD pathogenesis: β-amyloid (Aβ) and tau
protein. While the amyloid cascade theory has long dominated AD research, recent
developments have ignited debates about its centrality. Aβ plaques and
tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal
antibodies targeting Aβ, have been approved, albeit amidst controversy,
raising questions about the therapeutic efficacy of Aβ-focused
interventions. On the other hand, tau, specifically its hyperphosphorylation,
disrupts microtubule stability and contributes to neuronal dysfunction. Various
post-translational modifications of tau drive its aggregation into NFTs.
Emerging treatments targeting tau, such as GSK-3β and CDK5 inhibitors,
have shown promise in preclinical and clinical studies. Restoring the
equilibrium between protein kinases and phosphatases, notably protein
phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily
regulated by its phosphorylation state. Activation of tau-specific phosphatases
offers potential for mitigating tau pathology. The evolving landscape of AD drug
development emphasizes tau-centric therapies and reevaluation of the amyloid
cascade hypothesis. Additionally, exploring the role of neuroinflammation and
its interaction with tau pathology present promising research directions.
Keywords
Alzheimer’s disease - phosphorylation - tau - GSK-3β - CDK5
