Understanding the impact of cytoskeleton disruption on synaptic plasticity in Alzheimer's disease

Tau acetylation plays a critical role in the pathogenesis of Alzheimer's disease (AD) by disrupting cytoskeletal dynamics and synaptic plasticity. Acetylated tau aggregates contribute to the formation of neurofibrillary tangles (NFTs), leading to microtubule destabilization, impaired intracellular transport, and dysregulation of synaptic plasticity mechanisms. The cytoskeletal proteins, comprising microfilaments, microtubules, and intermediate filaments, are essential for maintaining neuronal structure, polarity, and signaling. The disruption of cytoskeletal integrity impairs dendritic spine formation, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor trafficking, mitochondrial transport, and autophagy, all crucial for synaptic plasticity. Glial cells, including astrocytes, oligodendrocytes, and microglia, also contribute to synaptic plasticity by interacting with neurons and regulating the extracellular environment. Acetylated tau aggregates interfere with these glial functions, exacerbating synaptic dysfunction. Moreover, cytoskeleton disruption impairs autophagy, mitochondrial dynamics, and function, leading to increased oxidative stress, reduced Adenosine triphosphate (ATP) production, and neuronal apoptosis. The accumulation of dysfunctional mitochondria further contributes to synaptic impairment and cognitive decline in AD. Understanding the complex interplay between tau acetylation, cytoskeletal dynamics, and synaptic plasticity is crucial for developing targeted therapeutic interventions to mitigate the progression of AD and other tauopathies.