Alternative splicing in Alzheimer's disease: Mechanisms, therapeutic implications, and 3D modeling approaches

Alzheimer's disease (AD) is characterized by progressive cognitive decline, memory loss, and behavioral changes. AD is pathologically marked by the accumulation of extracellular amyloid-β (Aβ) oligomers, amyloidogenic plaques, and intracellular neurofibrillary tangles. Amyloid-β protein precursor (AβPP) plays a central role in AD pathology, as it is cleaved by β-secretase and γ-secretase enzymes to generate Aβ peptides and oligomers which aggregate to form neurotoxic fibrils and plaques in the brain. Increased AβPP expression has been correlated to Aβ suggesting a larger role for AβPP function potentially through AβPP isoforms. Alternative splicing (AS) of APP pre-mRNA has emerged as a key regulatory mechanism influencing AβPP function through the generation of distinct isoforms. Similarly, the microtubule-associated protein tau (MAPT) is also subject to alternative splicing, producing isoforms that can contribute to hyperphosphorylation and neurodegeneration. In this review, we explore the role of APP alternative splicing and the regulation of its isoform expression in AD and other neurodegenerative disorders, with a focus on its potential impact on Aβ peptide production. We also discuss recent advances in therapies targeting dysregulated splicing in neurodegenerative diseases and their potential relevance to AD. Finally, we highlight the use of three-dimensional culture models as a platform to study AS regulation in AD and other neurodegeneration-related disorders.