Title : Stem-cell-based immunomodulation in Alzheimer’s disease: Targeting neuroinflammation beyond amyloid
Abstract:
Alzheimer’s disease (AD) has traditionally been characterized by amyloid and tau pathology; however, mounting evidence identifies chronic neuroinflammation as a central driver of disease progression rather than a secondary consequence. Persistent activation of microglia and astrocytes, coupled with blood–brain barrier dysfunction and peripheral immune infiltration, creates a self-amplifying inflammatory milieu that accelerates synaptic loss, neuronal death, and cognitive decline. Conventional therapeutic strategies have largely failed to adequately address this immune dysregulation. In this proposal, we examine emerging evidence supporting stem-cell–based interventions as a novel immunomodulatory strategy for AD. Rather than functioning primarily through neuronal replacement stem cells (mesenchymal, neural/progenitor, and induced pluripotent), cell-derived products exert their effects a paracrine signaling and extracellular vesicle–dependent pathways, thereby reprogramming maladaptive neuroinflammatory responses. We synthesize preclinical and translational findings demonstrating that stem-cell–derived secretomes suppress pro-inflammatory cytokine cascades, shift microglia toward repair-oriented phenotypes, attenuate astrocytic neurotoxicity, stabilize blood–brain barrier integrity, and modulate key inflammatory pathways including NF-κB, JAK/STAT, and the NLRP3 inflammasome. Importantly, these immunomodulatory effects correlate with preserved synaptic structure and cognitive improvement, often independent of amyloid burden. We also discuss current limitations, safety considerations, and challenges in clinical translation, including: product heterogeneity, biomarker validation, and regulatory complexity. Collectively, this proposal positions stem-cell–based immunomodulation as a promising, mechanistically grounded approach to disease modification in AD and highlights future directions toward immune-instructive and cell-free therapeutic platforms.
