At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gained interest as a potential therapy for neurodegenerative disorders like Alzheimer’s disease. This review aims to examine the role of the ketogenic diet in Alzheimer’s disease progression and to outline specific aspects of the nutritional profile providing a rationale for the implementation of dietary interventions as a therapeutic strategy for Alzheimer’s disease.

Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer’s disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer’s disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer’s disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer’s disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer’s disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer’s disease.

Background—: The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap , the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b , in atherosclerosis using knockout mice models. Methods and Results—: Gene-targeted mice for neighboring genes, including Mtap , Cdkn2a , p19Arf , and Cdkn2b , were each bred to mice carrying the human APO*E3 Leiden transgene that sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesions compared with wild-type mice (49623±21650 versus 18899±9604 μm ² per section [mean±SD]; P =0.01), with morphology similar to that of wild-type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles and CD4 ⁺ cell counts. The Cdkn2a knockout mice had smaller lesions compared with wild-type and heterozygous mice, and there were no significant differences in lesion size in p19Arf and Cdkn2b mutants compared with wild type. We observed extensive, tissue-specific compensatory regulation of the Cdkn2a and Cdkn2b genes among the various knockout mice, making the effects on atherosclerosis difficult to interpret. Conclusions—: Mtap plays a protective role against atherosclerosis, whereas Cdkn2a appears to be modestly proatherogenic. However, no relation was found between the 9p21 genotype and the transcription of 9p21 neighboring genes in primary human aortic vascular cells in vitro. There is extensive compensatory regulation in the highly conserved 9p21 orthologous region in mice.

Cystathionine β‐synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in humans, elevates plasma Hcy‐thiolactone and leads to connective tissue abnormalities that affect the cardiovascular and skeletal systems. However, the underlying mechanism of these abnormalities is not understood. Hcy‐thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N ‐homocysteinylated protein. Because lysine residues are involved in collagen cross‐linking, N ‐homocysteinylation of these lysines should impair cross‐linking. Using a Tg‐I278T Cbs ^−/− mousemodel of hyperhomocysteinemia(HHcy)which replicates the connective tissue abnormalities observed in CBS‐deficient patients, we found that N ‐Hcy‐collagen was elevated in bone, tail, and heartof Cbs ^−/− mice, whereas pyridinoline cross‐links were significantly reduced. Plasma deoxypyridinoline cross‐link and cross‐linked carboxyterminal telopeptide of type I collagen were also significantly reduced in the Cbs ^−/− mice. Lysine oxidase activity and mRNA level were not reduced by the Cbs ^−/− genotype. We also showed that collagen carries S‐linked Hcy bound to the thiol of N ‐linked Hcy. in vitro experiments showed that Hcy‐thiolactone modifies lysine residues in collagen type I α‐1 chain. Residue K ¹⁶⁰ , located in the nonhelical N ‐telopeptide region and involved in pyridinoline cross‐link formation, was also N ‐homocysteinylated in vivo . Taken together, our findings showed that N ‐homocysteinylation of collagen in Cbs ^−/− mice impairs its cross‐linking. These findings explain, at least in part, connective tissue abnormalities observed in HHcy.—Perla‐Kajan, J., Utyro, O., Rusek, M., Malinowska, A., Sitkiewicz, E., Jakubowski, H. N ‐Homocysteinylation impairs collagen cross‐linking in cystathionine β‐synthase‐deficient mice: a novel mechanism of connective tissue abnormalities. FASEB J. 30, 3810–3821 (2016) www.fasebj.org

Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by fibrosis and ECM deposition in skin and internal organs, autoimmunity, and changes in the microvasculature. Profiling of circulating miRNAs in serum has been found to be changed in pathological states, creating new possibilities for molecular diagnostics as blood-based biomarkers. This study was designed to identify miRNAs that are differentially expressed in SSc and might be potentially contributing to the disease etiopathogenesis or be used for diagnostic purposes. Thus, we compared the expression pattern of multiple miRNAs in serum of 10 SSc patients to 6 healthy controls using microarray analysis, and RT-qPCR to confirm the obtained results. In addition, bioinformatics analysis was performed to explore miRNAs target genes and the signaling pathways that may be potentially involved in SSc pathogenesis. Our study shows a different expression of 15 miRNAs in SSc patients. We identified that miR-4484, located on chromosome 10q26.2, was an 18-fold up-regulated in SSc patients compared to a control group. Bioinformatics analysis of the miR-4484 target genes and the signaling pathways showed that it might be potentially involved in the TGF-β signaling pathway, ECM-receptor interaction, and metalloproteinases expression. Based on the chromosomal location, the most interesting target gene of miR-4484 may be MMP-21. We found that the expression of MMP-21 significantly increased in SSc patients compared to healthy subjects (P < 0.05). Our results suggest that miR-4484, and MMP-21 might be novel serum biomarkers that may correspond to pathological fibrosis in SSc, but it needs to be validated in further studies.