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Abstract Background A common feature of Alzheimer's disease (AD) pathology is the abundance of activated microglia in neuritic plaques containing amyloid-beta protein (Aβ) and associated molecules including heparan sulfate proteoglycan (HSPG). Besides the role as pathological chaperone favouring amyloidogenesis, little is known about whether or not HSPG can induce microglial activation. Cultures of primary murine microglia were used to assess the effect of HSPG on production of proinflammatory molecules that are known to be present in neuritic plaques of AD. Results HSPG stimulated up-regulation of tumor necrosis factor-alpha (TNF-α), production of inducible nitric oxide synthase (iNOS) mRNA and accumulation of TNF-α protein and nitrite (NO2-) in a time- and concentration-dependent manner. The effects of HSPG were primarily due to the property of the protein core as indicated by the lack of microglial accumulation of TNF-α and NO2- in response to denaturated HSPG or heparan sulfate GAG chains (HS). Conclusion These data demonstrate that HSPG may contribute to chronic microglial activation and neurodegeneration seen in neuritic plaques of AD.

It is well established that several Homo sapiens populations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by the EPAS1 gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan/Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan WGS data and to shortlist those presenting Denisovan-like derived alleles that participate to the same functional pathways and are absent in populations of African ancestry, which are supposed to do not have experienced Denisovan admixture. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regards TBC1D1 , RASGRF2 , PRKAG2 , and KRAS , have plausibly contributed to shape the adaptive modulation of angiogenesis and of certain cardiovascular traits in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment., Competing Interests: GF, PA, MA, AD, PS, PC, MT, MD, GG, LN, AC, GM, DP, SS, MS No competing interests declared, (© 2023, Ferraretti, Abondio et al.)

Objectives: To report the case of a patient enduring migraine attacks preceded by hallucinatory olfactory symptoms, with characteristics which typically define migraine with aura (MWA)., Background: MWA accounts for about 30-40% of the total cases of migraine and is almost always preceded by visual disorders; and in rare cases migraine attacks are preceded by olfactory hallucinations which have not been so far recognized as a type of aura., Results: We describe a 51-year-old male whose migraine attacks are preceded, unusually for migraine sufferers, only by olfactory hallucinations; in 10% of the attacks, the olfactory symptoms are not followed by any pain but always appear with the same characteristics. These hallucinations began with the onset of a history of cephalea., Conclusion: This case suggests that olfactory hallucinations should be considered as actual pre-migraine symptoms, like visual symptoms or other disorders, and added to the criteria for the diagnosis of MWA., (© 2020 American Headache Society.)

Background: A common feature of Alzheimer's disease (AD) pathology is the abundance of activated microglia in neuritic plaques containing amyloid-beta protein (Abeta) and associated molecules including heparan sulfate proteoglycan (HSPG). Besides the role as pathological chaperone favouring amyloidogenesis, little is known about whether or not HSPG can induce microglial activation. Cultures of primary murine microglia were used to assess the effect of HSPG on production of proinflammatory molecules that are known to be present in neuritic plaques of AD., Results: HSPG stimulated up-regulation of tumor necrosis factor-alpha (TNF-alpha), production of inducible nitric oxide synthase (iNOS) mRNA and accumulation of TNF-alpha protein and nitrite (NO2-) in a time- and concentration-dependent manner. The effects of HSPG were primarily due to the property of the protein core as indicated by the lack of microglial accumulation of TNF-alpha and NO2- in response to denaturated HSPG or heparan sulfate GAG chains (HS)., Conclusion: These data demonstrate that HSPG may contribute to chronic microglial activation and neurodegeneration seen in neuritic plaques of AD.

MCP-1 levels are increased in CSF of patients with Alzheimer's disease (AD) compared with controls, suggesting a role in the development of dementia. Recently, a biallelic A/G polymorphism in the MCP-1 promoter at position -2518 has been found, influencing the level of MCP-1 expression in response to an inflammatory stimulus. The distribution of the A-2518G SNP was determined in 269 AD patients and in 203 healthy age matched controls, showing no differences between the two groups. On the contrary, a significant increase of MCP-1 serum levels in AD patients carrying at least one G mutated allele was observed. Moreover, the highest peaks of MCP-1 serum levels were present in patients carrying two G alleles. Stratifying by ApoE genotype, gender or age at onset, no differences in both allele frequency and MCP-1 serum concentration were observed. The A-2518G polymorphism in MCP-1 gene does not seem to be a risk factor for the development of AD, but its presence correlates with higher levels of serum MCP-1, which can contribute to increase the inflammatory process occurring in AD.

This study describes the infiltration and death of monocyte/macrophages and concomitant endoneurial expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) and neurotrophin receptor p75 (p75NTR) in the sciatic nerve at the early phases of experimental diabetic neuropathy induced in Lewis rats by streptozotocin (STZ) intraperitoneal injection. Immunocytochemistry and single nerve fiber immunostaining showed the presence of macrophages in diabetic nerves by weeks 2 and 3 after STZ administration, and the 15% of these cells were TUNEL positive. IL-1beta was evident in scattered macrophages, and along few isolated nerve fibers until week 5, when it became undetectable, in concomitance with complete endoneurial clearance of macrophages. p75NTR showed an up-regulation in the sciatic nerve of diabetic rats that began by week 3 after STZ administration, reached its peak by week 5, and returned then to a barely detectable level by week 6. These findings seem to indicate that macrophages and IL-1beta may be involved in the pathogenesis of diabetic neuropathy, participating not only to nerve damage but also to the promotion of an attempt of regeneration via p75NTR induction.

This study reports that in Schwann cell tissue culture the administration of the two pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma), at different dosages, singly or in combination, can induce apoptosis and/or mitosis. Schwann cell apoptosis was maximal within 24 h of stimulation with 50 U/ml of IFN-gamma, while proliferation was at its peak within 24 h with 10 U/ml IL-1 beta, and both processes decreased progressively by 48 and 72 h. Moreover, the combination of the two cytokines did not show any synergistic effect. These data can be interpreted as a possible involvement of pro-inflammatory cytokines not only in myelin disruption but also in promoting remyelination.