Researchers Discover New Insights Into Neuroinflammation in Alzheimer’s Disease

In a recent study published in the Journal of Neuroinflammation, researchers from China were able to identify a new target to address the Neuroinflammation found in patients with Alzheimer’s disease.

Neuroinflammation, characterized by excessive glial activation and overproduction of proinflammatory cytokine and chemokines, plays a critical role in the pathogenesis of neurodegeneration in Alzheimer’s disease (AD). Inhibition of glial activation is shown to improve synaptic dysfunction and behavioral deficits in AD animal models.

Amyloid-β (Aβ) peptides are key molecules in AD pathology as they aggregate to form amyloid plaques, the primary neuropathological hallmarks of AD. Aggregated Aβ peptides, in the forms of fibrils and oligomers, are prominent triggers for microglial activation. Accumulating evidence demonstrates that the redox-active Cu(II) ions can be coordinated with other molecules leading to formation of the Cu(II)-Aβ complex. The concentration of extracellular Cu(II), especially within the amyloid plaques, is markedly elevated in the brains of patients with AD.

The transcription factor nuclear factor (NF)-κB has been identified as a key regulator of cellular immune responses, including microglial activation. NF-κB activation can be directly driven by reactive oxygen species (ROS). ROS, derived from NADPH oxidase (NOX) or mitochondria, play important roles in regulating microglial responses to various stimuli.

With the aim of determining if whether Cu(II) coordination is able to enhance the effect of Aβ on microglial activation and the subsequent neurotoxicity, and to examine if this effect involves NF-κB and ROS, and where these ROS are generated, in their study titled “Cu(II) enhances the effect of Alzheimer’s amyloid-β peptide on microglial activation,” Juan Li from the Department of Pharmacology at Shanghai Jiao Tong University School of Medicine in China along with colleagues incubated Aβ peptides with Cu(II) and assessed tumor necrosis factor-α (TNF-α), nitric oxide levels, extracellular hydrogen peroxide and mitochondrial superoxide.

The results showed that Cu(II) is a cofactor promoting the effect of Aβ on microglial activation and the subsequent neurotoxicity. Results also showed that the Cu(II)-Aβ-triggered microglial activation may involve NF-кB activation and mtROS production.

The researchers concluded that these results further support the notion that metal ion-induced Aβ aggregation might be important in microgliamediated neuroinflammation and might provide a novel anti-inflammatory strategy for patients with AD.