Brain peptides in Alzheimer's disease - pathophysiology and therapeutic advances.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and hallmark neuropathological features, including extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. Peptides occupy a central position in AD pathobiology: pathogenic species such as Aβ oligomers and tau-derived fragments drive synaptic failure, mitochondrial dysfunction, and neuroinflammation, whereas several endogenous neuropeptides exert compensatory neuroprotective, trophic, or homeostatic effects. In parallel, advances in peptide chemistry and structural biology have enabled the design of aggregation inhibitors, receptor-selective neuropeptide analogues, and cell-penetrating or brain-targeted peptide conjugates that modulate key pathways, including proteostasis, insulin and incretin signaling, neurotrophic support, and microglial activation. This review integrates current evidence on how brain peptides contribute to AD pathophysiology, summarizes recent progress in peptide-based therapeutic strategies and delivery platforms, and critically examines the remaining barriers to clinical translation, including blood-brain barrier penetration, metabolic stability, off-target effects, and the need for biomarker-guided patient stratification. By highlighting both mechanistic insights and translational advances, the review article outlines how next-generation engineered peptide therapeutics, used alone or in combination with existing disease-modifying agents, may help reshape the future landscape of AD diagnosis, prevention, and treatment.