See Cunha (doi:10.1093/brain/awz335) for a scientific commentary on this article. Carvalho et al. provide clues to the onset of immune dysregulation underlying early synaptic loss in Alzheimer’s disease and tauopathies, by linking overactivation of adenosine A2A receptors in tau pathology to a particular microglial signature (upregulation of C1q and TREM2) allied to the loss of glutamatergic synapses and cognitive deficits.

AbstractSince Alzheimer’s disease was first described in 1907, many attempts have been made to reveal its main cause. Nowadays, two forms of the disease are known, and while the hereditary form of the disease is clearly caused by mutations in one of several genes, the etiology of the sporadic form remains a mystery. Both forms share similar sets of neuropathological and molecular manifestations, including extracellular deposition of amyloid-beta, intracellular accumulation of hyperphosphorylated tau protein, disturbances in both the structure and functions of mitochondria, oxidative stress, metal ion metabolism disorders, impairment of N-methyl-D-aspartate receptor-related signaling pathways, abnormalities of lipid metabolism, and aberrant cell cycle reentry in some neurons. Such a diversity of symptoms led to proposition of various hypotheses for explaining the development of Alzheimer’s disease, the amyloid hypothesis, which postulates the key role of amyloid-beta in Alzheimer’s disease development, being the most prominent. However, this hypothesis does not fully explain all of the molecular abnormalities and is therefore heavily criticized. In this review, we propose a hypothetical model of Alzheimer’s disease progression, assuming a key role of age-related mitochondrial dysfunction, as was postulated in the mitochondrial cascade hypothesis. Our model explains the connections between all the symptoms of Alzheimer’s disease, with particular attention to autophagy, metal metabolism disorders, and aberrant cell cycle re-entry in neurons. Progression of the Alzheimer’s disease appears to be a complex process involving aging and too many protective mechanisms affecting one another, thereby leading to even greater deleterious effects.

Myeloperoxidase (MPO) is a challenging molecular target which, if put under control, may allow regulating the development of inflammatory reactions associated with oxidative/halogenative stress. In this paper, a new kinetic method for assaying the halogenating activity of MPO is described. The method is based on measuring the rate of iodide-catalyzed oxidation of celestine blue B (CB) by oxygen and taurine N-chloramine (bromamine). The latter is produced in a reaction of taurine with HOCl (HOBr). CB is not a substrate for the peroxidase activity of MPO and does not react with hydrogen peroxide and superoxide anion radical. Taurine N-chloramine (bromamine) reacts with CB in molar ratio of 1:2. Using the new method, we studied the dependence of MPO activity on concentration of substrates and inhibitors. The specificity of MPO inhibition by non-proteolyzed ceruloplasmin is characterized. The inhibition of taurine N-chloramine production by neutrophils and HL-60 cells in the presence of MPO-affecting substances is demonstrated. The new method allows determining the kinetic parameters of MPO halogenating activity and studying its inhibition by various substances, as well as screening for potential inhibitors of the enzyme.

Purinergic signaling regulates neuronal and glial cell functions in the healthy CNS. In neurodegenerative diseases, purinergic signaling becomes dysregulated and can affect disease-associated phenotypes of glial cells. In this review, we discuss how cell-specific expression patterns of purinergic signaling components change in neurodegeneration and how dysregulated glial purinergic signaling and crosstalk may contribute to disease pathophysiology, thus bearing promising potential for the development of new therapeutical options for neurodegenerative diseases.