Neurodegenerative Changes in the Structural and Ultrastructural Organization in the Pyriform Cortex of 5xFAD Transgenic Mice

Journal of Evolutionary Biochemistry and Physiology - Analysis of pathological changes in the structural and functional organization of the pyriform cortex in mice of the 5xFAD line, which models...     

Effect of Global Brain Ischemia on Amyloid Precursor Protein Metabolism and Expression of Amyloid-Degrading Enzymes in Rat Cortex: Role in Pathogenesis of Alzheimer’s Disease

Biochemistry (Moscow) - The incidence of Alzheimer’s disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic...     

Activation of neutral sphingomyelinase by IL-1beta requires the type 1 interleukin 1 receptor

The cytokine interleukin 1beta (IL-1beta) plays an important role in host defence reactions and neuro-immune interactions but it is still not clear which of the two interleukin 1 receptor subtypes is coupled to activation of neutral sphingomyelinase (nSMase) by IL-1beta. To investigate involvement of neutral sphingomyelinase (nSMase) in central IL-1beta effects we used P(2)fractions of brain cerebral cortex from wild-type mice and mice deficient in the type 1 IL-1 receptor. IL-1beta (human, recombinant) was shown to activate, in a dose-dependent manner, nSMase in the P(2)brain fraction of the wild-type mice while in the knock-out mice the stimulatory effect of IL-1beta on nSMase was absent. In the presence of an IL-1 receptor antagonist (IL-1ra), IL-1beta did not activate nSMase either in the cortex of wild-type or knock-out mice. These data suggest that nSMase, a key enzyme of the sphingomyelin signal transduction pathway, might be involved in IL-1beta signalling in the brain and that activation of the enzyme requires the IL-1 receptor type 1.     

Does acetylcholinesterase secretion involve an ADAMs-like metallosecretase?

The ADAMs (A Disintegrin And Metalloprotease-like) family is a large and rapidly expanding group of metalloproteinases with structural similarity. They are normally characterized by the presence of a proteolytic domain and disintegrin and signalling domains. Although 21 ADAMs proteins have been already cloned to date, in most cases their natural substrates are unknown. The best characterized representative of the mammalian ADAMs family is the TNF- converting enzyme (TACE). TACE is an integral membrane metalloproteinase that causes the secretion of the active form of TNF- from its plasma membrane precursor and thus can be regarded as a membrane protein secretase. Secretion of membrane proteins is a very well documented biological phenomenon and was demonstrated for a diverse range of membrane proteins, two examples being angiotensin converting enzyme (ACE) and Alzheimer's amyloid precursor protein (APP). ACE and APP secretion was shown to possess substantial similarity with the secretion of TNF-. In the present study, we have attempted to demonstrate that a metalloproteinase might be involved in the shedding of another membrane-bound protein – acetylcholinesterase (AChE). Secretion of AChE by human neuroblastoma SH-SY5Y cells was found to be inhibited by a selective hydroxamate metalloproteinase inhibitor batimastat (20 M), and stimulated by carbachol (20 M), which have previously been shown to regulate the activity of APP -secretase in a similar manner. The role of ADAMs proteins in the shedding of molecules from the cell surface is discussed.     

Study of heterogeneity of chromatin endonuclease fragments, using fractionation by step-wise endonucleolysis

Isolated nuclei from rat liver were incubated at different time intervals under conditions, optimal for manifestation of the Ca, Mg-dependent endonuclease activity. After each of the 6 endonucleolyses chromatin was extracted and 6 chromatin fractions (I--VI) and "residual" chromatin were collected. A comparative analysis of the "early" (I--III) and "late" chromatin fractions revealed an increased RNA content in the "late" fractions and changes in the composition of the non-histone proteins. Electrophoresis in acrylamide gel concentration gradient demonstrated that fractions I--III predominantly contain high molecular weight fragments whereas fractions IV-VI are represented by highly fragmented chromatin. Each fraction was characterized by peculiar shapes of alkaline denaturation curves and by heterogeneity of charges of their constituent chromatin fragments.     

Does acetylcholinesterase secretion involve an ADAMs-like metallosecretase?

Summary The ADAMs (A Disintegrin And Metalloprotease-like) family is a large and rapidly expanding group of metallo-proteinases with structural similarity. The are normally characterized by the presence of a proteolytic domain and disintegrin and signalling domains. Although 21 ADAMs proteins have been already cloned to date, in most cases their natural substrates are unknown. The best characterized representative of the mammalian ADAMs family is the TNF-α converting enzyme (TACE). TACE is an integral membrane metalloproteinase that causes the secretion of the active form of TNF-α from its plasma membrane precursor and thus can be regarded as a membrane protein secretase. Secretion of membrane proteins is a very well documented biological phenomenon and was demonstrated for a diverse range of membrane proteins, two examples being angiotensin converting enzyme (ACE) and Alzheimer's amyloid precursor protein (APP). ACE and APP secretion was shown to possess substantial similarity with the secretion of TNF-α. In the present study, we have attempted to demonstrate that a metalloproteinase might be involved in the shedding of another membrane-bound protein—acetylcholinesterase (AChE). Secretion of AChE by human neuroblastoma SH-SY5Y cells was found to be inhibited by a selective hydroxamate metalloproteinase inhibitor batimastat (20 μM), and stimulated by carbachol (20 μM), which have previously been shown to regulate the activity of APP α-secretase in a similar manner. The role of ADAMs proteins in the shedding of molecules from the cell surface is discussed.     

Effect of an inhibitor of alpha-secretase metabolizing amyloid precursor protein on memory in rats

Intracortical administration of 10(-4) M batimastat, a specific inhibitor of one of metalloproteinases metabolizing amyloid precursor protein, namely alpha-secretase, to adult rats resulted in a decrease in the number of correct runs in a one-level 8-arm maze down to 92.78 +/- 1.03% of the control values (p < 0.01) already 60 min after an injection. The effect of a single injection of the inhibitor to adult rats did not have a prolonged character. However, injections of batimastat into the cortex of brain hemispheres of rats during early postnatal ontogenesis (5th and 7th days after birth) resulted in considerable deterioration of 8-arm maze orientation of these animals at adult age (90.92 +/- 2.21% of correct runs, p < 0.001) compared to control animals. The findings suggest an important role of alpha-secretase in memorization. A possible role of alpha-secretase in memory and pathogenesis of Alzheimer's disease is discussed.