Pharmacological targeting of neuroimmune–synaptic interactions in Alzheimer's disease: Integrating NETosis, microglia, and synaptic vulnerability
Journal
Current Opinion in Pharmacology
Journal Volume
90
Start Page
102650
ISSN
1471-4892
Date Issued
2026-10
Author(s)
Juanlu, Chen
Abstract
Alzheimer's disease (AD) is increasingly recognized as a disorder involving interacting neuroimmune, glial, vascular, and synaptic processes that are not fully captured by single-pathway therapeutic models. Although anti-amyloid monoclonal antibodies slow clinical progression in selected early amyloid-positive patients, their benefit remains stage-dependent, monitoring-intensive, and incomplete with respect to downstream neural dysfunction. Clinically, vulnerable older adults may show abrupt cognitive decline after pneumonia-related hospitalization or other severe infections. This observation raises a pharmacological question: whether infection-triggered peripheral immune events activate modifiable risk processes before they become sustained neuroimmune and synaptic dysfunction. NETosis is one candidate mechanism linking peripheral inflammatory stress to endothelial injury, blood–brain barrier vulnerability, myeloid priming, and microglial dysregulation. Acute infection may represent a high-intensity peripheral NETosis-related trigger, whereas periodontitis provides a chronic, low-grade, neutrophil-rich, microbially driven, clinically measurable, and modifiable peripheral inflammatory model. We propose a node-based pharmacological framework organized around NETosis-associated immune amplification, microglial state dysregulation, and synaptic vulnerability. Selected phytochemicals are examined as node-aligned pharmacological probes rather than validated AD therapeutics: baicalin and hesperidin for NETosis-associated immune amplification, berberine for microglial state modulation, and catalpol as a synapse-proximal candidate.
Publisher
Elsevier BV
Type
review article