NEUROINFLAMMATION AND MICROBIAL ACTIVATION AS A CENTRAL MECHANISM IN THE PROGRESSION OF ALZHEIMER’S DISEASE: A REVIEW OF EMERGING THERAPEUTIC TARGETS

Abstract

Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative dementia, clinically characterized by progressive cognitive decline and, histopathologically, by the accumulation of β-amyloid plaques and neurofibrillary tangles. In recent decades, understanding of the pathophysiological mechanisms of AD has expanded beyond the amyloid hypothesis, highlighting chronic neuroinflammation and microglial activation as central factors in disease progression. Persistent activation of glial cells can exacerbate neuronal loss through the release of pro-inflammatory cytokines, reactive oxygen species, and alterations in the blood-brain barrier, in addition to suggesting the influence of microbial factors in modulating the gut-brain axis. The objective is to gather and critically analyze recent scientific production on the mechanisms of neuroinflammation and microbial activation in AD, focusing on potential emerging therapeutic targets that aim to modulate the inflammatory response and slow disease progression. This work consists of a qualitative, descriptive, and analytical literature review. National and international publications indexed in the SciELO, LILACS, PubMed, Scopus, and Web of Science databases, published between 2019 and 2024, were included, prioritizing systematic review articles, in vitro and in vivo experimental studies, and ongoing clinical trials. The descriptors used included “Alzheimer’s disease,” “neuroinflammation,” “microglial activation,” “microbiota,” and “therapeutic targets.” The reviewed evidence reinforces that chronic microglial activation plays a dual role: while an initial microglial response is neuroprotective, its sustained activation favors a neurotoxic environment. Cytokines such as TNF-α, IL-1β, and IL-6 perpetuate the inflammatory cycle, contributing to synaptic dysfunction and neuronal death. At the same time, recent studies highlight the possible participation of the gut microbiota in modulating neuroinflammation through neuroactive metabolites and lipopolysaccharide (LPS) translocation, suggesting the gut-brain axis as a potential target. Several therapeutic approaches are emerging in this context: selective NLRP3 inflammasome inhibitors, Toll-like receptor (TLR) modulators, anti-amyloid monoclonal antibodies with immunomodulatory action, and probiotics capable of restoring microbial balance. Preliminary clinical trials have shown promising results, but there are still gaps in the long-term efficacy and safety of these interventions. Neuroinflammation and microbial activation are central elements in the pathogenesis and progression of AD, expanding the therapeutic horizon beyond the traditional focus on β-amyloid. A deeper understanding of inflammatory pathways and the gut-brain interaction may support the development of more effective and personalized therapies capable of slowing the course of the disease and improving patients’ quality of life. Translational research and robust clinical trials are essential to consolidate these targets as viable therapeutic strategies.