Advances in phytochemical modulation of protein aggregation in neurodegenerative diseases

Protein aggregation and misfolding are central pathological events underlying major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related proteinopathies. The aberrant aggregation of amyloid-β, tau, and α-synuclein generates toxic oligomeric and fibrillar species that disrupt proteostasis, impair synaptic function, promote oxidative stress and neuroinflammation, and ultimately drive progressive neuronal loss. This review critically summarizes recent advances in plant-derived secondary metabolites with anti-aggregation properties, emphasizing their structural diversity, molecular mechanisms, structure-activity relationships, and translational potential. Current findings demonstrate that polyphenols, flavonoids, terpenoids, alkaloids, curcuminoids, and secoiridoids inhibit protein aggregation through multiple complementary mechanisms, including direct modulation of amyloidogenic proteins and restoration of proteostasis via molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, mitochondrial protection, and suppression of neuroinflammatory signaling. Emerging evidence further demonstrates that rational structural optimization, hybrid molecule design, and nanotechnology-based delivery systems can substantially improve the pharmacokinetic limitations of these compounds. Overall, the accumulated evidence indicates that phytochemicals possess multitarget therapeutic potential by simultaneously reducing protein aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, thereby offering broader neuroprotection than single-target approaches. Nevertheless, limited bioavailability, poor blood-brain barrier penetration, interspecies variability, and insufficient clinical validation continue to impede translation. By integrating mechanistic evidence with recent advances in medicinal chemistry and drug delivery, this review highlights promising strategies to accelerate the development of phytochemical-based therapeutics for protein aggregation-associated neurodegenerative diseases. Unlike previous studies that primarily summarize anti-amyloid phytochemicals, this review integrates recent mechanistic insights into protein aggregation, proteostasis regulation, medicinal chemistry optimization, structural biology, and translational challenges across multiple neurodegenerative proteinopathies.