This review analyzes the role of TNF-α and its increase in biological fluids in mild cognitive impairment, and Alzheimer’s disease (AD). The potential inhibition of TNF-α with pharmacological strategies paves the way for preventing AD and improving cognitive function in people at risk for dementia. We conducted a narrative review to characterize the evidence in relation to the involvement of TNF-α in AD and its possible therapeutic inhibition. Several studies report that patients with RA and systemic inflammatory diseases treated with TNF-α blocking agents reduce the probability of emerging dementia compared with the general population. Animal model studies also showed interesting results and are discussed. An increasing amount of basic scientific data and clinical studies underscore the importance of inflammatory processes and subsequent glial activation in the pathogenesis of AD. TNF-α targeted therapy is a biologically plausible approach for cognition preservation and further trials are necessary to investigate the potential benefits of therapy in populations at risk of developing AD.

Several studies indicate that the development of Alzheimer's disease (AD) has strong interactions with immune mechanisms within the brain, indicating a close association between inflammation in the central nervous system and the progression of neurodegeneration. Despite considerable progress in understanding the inflammatory aspects of AD, several of them remain unresolved. Pro-inflammatory cytokines and microglia are pivotal components in the inflammatory cascade. Among these, the role of interleukin-8 (IL-8) in neurodegeneration seems complex and multifaceted, involving inflammation, neurotoxicity, blood-brain barrier disruption, and oxidative stress, and is still poorly characterized. We conducted a review to describe the evidence of IL-8 involvement in AD. IL-8 is a cytokine known for its proinflammatory properties and typically produced by macrophages, predominantly functions as a chemotactic signal for attracting neutrophils to inflamed sites in the bloodstream. Interestingly, IL-8 is also present in the brain, where it is primarily released by microglia in response to inflammatory signals. This review aims to provide a comprehensive overview of the structure, function, and regulatory mechanisms of IL-8 relevant to AD pathology.

Background: Neurofilament light chains (NfL) represent reliable serum biomarkers of neuroaxonal injury. Due to their low serum levels, precise detection methods are critical. This study aimed to scrutinize the comparability of two techniques: Single Molecule Array (SiMoA) and Ella automated immunoassay, analyzing serum NfL levels in ATTRv presymptomatic subjects and polyneuropathy patients.Methods: Blood samples were processed and analyzed using commercial Ella and SiMoA kits. Statistical analysis included the Wilcoxon signed‐rank test, Spearman correlation, Bland–Altman, and Passing‐Bablok regression. ANCOVA models were used to compare NfL levels between cohorts.Results: The study measured serum NfL levels in 55 symptomatic and 55 presymptomatic ATTRv subjects. Median NfL concentrations were significantly higher with Ella (median 27.5 pg/mL) than SiMoA (median 15.9 pg/mL). Both methods showed a strong positive correlation (r = 0.8, p < 0.001), but Ella overestimated NfL by 42%. Bland–Altman analysis revealed a mean bias of 15.4 pg/mL, with limits of agreement between −41.1 and 72.0 pg/mL. The slope of the Passing–Bablok regression line was 0.58, and the intercept was 3.48 pg/mL, suggesting that the Ella platform tends to overestimate NfL concentrations compared to the SiMoA platform, especially at higher concentrations. Both methods effectively distinguished presymptomatic from symptomatic patients (p < 0.001 for both).Conclusions: Our findings underscore that both platforms are effective in measuring serum NfL, with Ella consistently overestimating, especially at higher concentrations. The difference between the two platforms must be taken into account when deeming the concentrations as pathological or normal, as well as when conducting longitudinal studies.

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same mutation. Historically, ATTRv amyloidosis has been viewed as a non-inflammatory disease, mainly due to the absence of any mononuclear cell infiltration in ex vivo tissues; nevertheless, a role of inflammation in its pathogenesis has been recently highlighted. The immune response may be involved in the development and progression of the disease. Fibrillary TTR species bind to the receptor for advanced glycation end products (RAGE), probably activating the nuclear factor κB (NF-κB) pathway. Moreover, peripheral blood levels of several cytokines, including interferon (IFN)-gamma, IFN-alpha, IL-6, IL-7, and IL-33, are altered in the course of the disease. This review summarizes the current evidence supporting the role of the immune response in ATTRv amyloidosis, from the pathological mechanisms to the possible therapeutic implications.

Background/Objectives: Given the multifaceted role of estrogen hormones in skeletal muscle pathophysiology and their well-established immunomodulatory properties, this study aimed to characterize the expression of the G-protein-coupled estrogen receptor (GPER) in patients with inflammatory myopathies (IM). Methods: Immunohistochemical analysis was performed on muscle biopsies from 13 patients with IM, 11 with non-inflammatory myopathies (N.IM), and 5control subjects. Intergroup differences in GPER score were statistically evaluated. We performed an analysis based on the Visual Analog Scale (VAS). The scoring system evaluates overall pathology (VAS score) based on four distinct components: inflammation, vascular involvement, myopathic changes, and connective tissue alterations. Results: Immunolocalization analysis demonstrated that GPER is constitutively expressed in human skeletal muscle and is upregulated in IM. Enhanced expression included both sarcolemmal and intracellular membrane localization. Notably, GPER upregulation showed a positive correlation with the severity of tissue inflammation. The IM group had significantly higher VAS scores compared to both the N.IM and control groups. Conclusions: We provide the first histopathological characterization of GPER expression in human skeletal muscle. In IM, GPER upregulation may play a protective role by negatively modulating the release of inflammatory mediators, as suggested by experimental evidence from other models of inflammation. The emerging therapeutic development of GPER agonists may represent a promising avenue for the treatment of inflammatory myopathies.