Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer's disease: phytochemicals as neuroprotective agents.

Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer's disease (AD), preceding extensive neuronal loss. Although amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca2+) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, Aβ alters the cargo carried by exosomes, facilitating the spread of pathogenic Aβ and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.