Is Innate Memory a Double-Edge Sword in Alzheimer's Disease? A Reappraisal of New Concepts and Old Data.

An emergent concept in immunology suggests that innate immune system is capable to undergo non-specific long-term responses and to provide resistance by modifying the reactivity to sequential pathogen challenge. This phenomenon, named innate memory, involves epigenetic, and metabolic reprogramming of innate immune cells. Current literature shows that the innate memory process has a mainly beneficial role in host defense, but sometimes can exert detrimental effects, as common in many diseases. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and dementia. Accumulating findings demonstrate that inflammation is involved in AD pathogenesis and progression and recent genetic and functional data confirm the driving role of the innate immune component in the disease. Furthermore, AD patients show high burden of the most relevant infectious agents and up-regulation of inflammatory features in their innate immune cells, including an activated, or "primed" status of myeloid phagocytic cells in both brain and periphery, resembling trained immunity conditions. Thus, it is conceivable that AD innate cells may be firstly involved in the attempt to resolve recurrent/persistent inflammation but then acquire a trained phenotype mostly unable to maintain the immune regulation, leaving uncontrolled or sometimes supporting the progression of neurodegeneration. The present review aims to summarize evidence evoking innate immune memory mechanisms in AD, and to interpret their potential role, either protective or harmful, in disease progression. A better understanding of such mechanisms will provide a fertile ground for development of novel diagnostic, and therapeutic pathways in AD cure.

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment.

Alzheimer's disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1ß, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFß), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.

IL-18 Serum Levels and Variants of the Serotonin Transporter Gene Are Related to Awareness of Emotions in Healthy Subjects: A Preliminary Study.

OBJECTIVE: Interaction between the nervous and immune systems may influence emotions, ultimately affecting human health. Cytokines may play a role in developing emotional dysregulation as in alexithymia, a personality construct characterized by the subclinical inability to identify and describe emotions, often associated with several psychiatric and psychosomatic disorders. The proinflammatory cytokine IL-18, with a recognized role in brain functions, may influence serotonin metabolism and appears to be associated with alexithymia. Healthy individuals carrying the long allele (L) of the serotonin transporter gene polymorphic region (5-HTTLPR), and thus having lower concentrations of serotonin in the synaptic cleft, show a greater tendency toward alexithymia, with some gender differences. To explore a potential physiological interaction between IL-18, serotonin neurotransmission, and alexithymia, we investigated whether IL-18 serum levels and 5-HTTLPR are linked to alexithymic traits in healthy subjects. METHODS: We measured IL-18 serum levels in 115 Italian-Caucasian healthy subjects genotyped for 5-HTTLPR allele variants, divided by gender and assessed for alexithymia scores using the 20-item Toronto Alexithymia Scale. RESULTS: IL-18 levels are significantly more elevated in individuals with the LL genotype (n = 25) than in carriers of the short allele (n = 90, p = 0.0073). Specifically, in LL males (n = 11), i.e., the group with the most relevant increase in IL-18, cytokine values positively correlated with difficulty identifying feelings, which is a component of alexithymia (r = 0.634, p = 0.036). CONCLUSIONS: These results indicate a possible novel interaction between IL-18 and the serotoninergic system to mediate emotional unawareness, suggesting putative biological predictors of emotional dysregulation, which in turn can act as a risk factor for a variety of medical conditions in susceptible subjects.

LC-MS/MS simultaneous analysis of allopregnanolone, epiallopregnanolone, pregnanolone, dehydroepiandrosterone and dehydroepiandrosterone 3-sulfate in human plasma.

AIM: Several neuropsychopharmacological properties have been attributed to the 3α-reduced pregnane steroids, allopregnanolone and pregnanolone, as well as to dehydroepiandrosterone sulfate because of their ability to modulate γ-aminobutyric acid (GABAA) receptors in the CNS. In order to understand better their role in several mechanisms in CNS, a new methodology is proposed to monitor these compounds in human plasma. Methodology & results: The analytes were first derivatized with 2-hydrazinopyridine and extracted from plasma using SPE. Then, the compounds were separated and detected by LC-MS/MS. A mobile phase of formic acid (0.1%) in water and methanol through a gradient of composition and a flow rate of 0.3 ml min-1 resulted in good separations of the analytes. Linear responses in wide range of concentrations and LOQs ranging from 10 (dehydroepiandrosterone 3-sulfate) to 40 pg ml-1 (dehydroepiandrosterone) were obtained in <9 min. The method proposed has been validated and then applied to monitor these neurosteroids in plasma samples from ten volunteers. CONCLUSION: For the first time, a straightforward and reliable method for the chromatographic separation of allopregnanolone, epiallopregnanolone and pregnanolone, as well as of dehydroepiandrosterone and dehydroepiandrosterone 3-sulfate was carried out, with optimal accuracy, sensitivity and specificity.