Neuroprotective or Destructive? A Comprehensive Review on Plant Peptides for Neurodegenerative Disease

Abstract

Progressive neuronal death caused by oxidative stress, aberrant protein aggregation, cholinergic deficits, neuroinflammation, and dysbiosis of the gut‐brain axis are attributes of neurodegenerative disorders (NDs), which include Alzheimer's and Parkinson's diseases. The investigation of novel Phyto therapeutics is prompted by the fact that conventional therapies only provide symptomatic relief without altering the disease. The aim of this study is to evaluate plant‐derived bioactive peptides critically for their dualistic neuroprotective versus neuro‐destructive potential in NDs, clarifying the underlying molecular mechanisms and translational barriers. The systematic review process followed the PRISMA 2020 guidelines to ensure transparency and reproducibility. A review of literature in Medline, EMBASE, PubMed, Scopus, and ScienceDirect was carried out from 2006 to 2026. Procedures for peptide isolation and purification, sequence activity relationship analyses, in vitro/in vivo functional tests (ROS scavenging, cholinesterase inhibition, tau phosphorylation, Aβ fibrillogenesis, cytokine profiling, microbiota modulation), and toxicological evaluations were all included in the inclusion criteria. Neuroprotective peptides activate the Nrf2/HO‐1 antioxidant cascade, inhibit GSK‐3β/JNK‐mediated tau hyperphosphorylation, impede Aβ aggregation, suppress acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activity, upregulate neurotrophins (BDNF, NGF), and restore microbial homeostasis via short‐chain fatty acid modulation by increasing Bifidobacterium/Lactobacillus abundance and decreasing inflammatory Firmicutes. Immunomodulatory sequences fine‐tune microglial clearance. Inspite of their size and polarity, several plant peptides can traverse the BBB primarily through receptor‐ and adsorptive‐mediated transcytosis, enabling central delivery. Conversely, cyclotides and thionins exhibit dose‐dependent hemolysis, cardiotoxicity, and immunogenic risk. Despite screening similar phytochemical motifs such as cationicity, hydrophobic residues, and ß‐sheet propensity protective peptides prevent aggregation and misfolding, while destructive peptides exploit same features to induce membrane disruption and cytotoxicity. Major challenges include scalable purification, gastrointestinal stability, and immunogenicity. Integrative strategies computational docking, targeted nanoencapsulation and peptide cyclization are imperative to enhance bioavailability, target specificity, and safety, thereby accelerating the translation of plant peptides into precision Phyto therapeutics for neurodegenerative diseases.