Alzheimer's Disease (AD) Neuroinflammation and Excitotoxicity: Mechanisms and New Treatment Approaches

Abstract

According to the World Health Organization, Alzheimer's Disease (AD) is an escalating global health crisis that requires more study and better diagnostic methods, with dementia cases projected to reach 131 million by 2050. Widespread neuroinflammation is central to the pathophysiological pathways of AD, a complex neurodegenerative disease. Microglia are activated by tau protein phosphorylation and amyloid-beta plaque formation, which starts the neuroinflammatory process. Reactive Oxygen Species (ROS) and other inflammatory mediators, such as cytokines, are released by activated microglia and can start a feed-forward cycle that exacerbates brain injury and cell death. Excitotoxicity also results in mitochondrial dysfunction and oxidative stress, both of which lead to neuronal death. Dysregulated glutamate signaling mediates this. This review aims to evaluate innovative therapeutic strategies targeting neuroinflammatory and excitotoxic pathways. One of the innovative ways to enhance neuroprotection and reduce oxidative damage at the same time is to alter microglial activation. Anti-inflammatory treatments, such as Non-Steroidal Anti-Inflammatory medications (NSAIDs), and treatments that target the inflammasome and Tumor Necrosis Factor-alpha (TNF-α) pathways are meant to alleviate chronic inflammation. In order to prevent neurodegeneration, the treatment of excitotoxicity aims to maintain calcium homeostasis and regulate glutamate. A systematic literature search was conducted across the electronic databases, including PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar, covering the period from 1991 to 2025. Keywords used included "Alzheimer’s disease," "neuroinflammation," "microglial activation," "excitotoxicity," and "kinase inhibitors." Studies were selected based on inclusion criteria focused on molecular mechanisms and clinical/pre-clinical therapeutic interventions. A total of 136 relevant peerreviewed articles and clinical trial reports were retrieved for this review. These key results show that using anti-inflammatory drugs and therapies that support calcium balance can effectively interrupt the pathological cycle between neuroinflammation and excitotoxicity. To take care of patients and find new ways to treat them without harming their neurons, we need to do more research. Simultaneously targeting multiple interconnected pathogenic pathways is a promising therapeutic strategy for reducing neurodegeneration, maintaining cognitive function, and delaying the onset and progression of dementia.