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Supplementary MaterialsFIGURE S1: Olfactory -Amyloid pathology increases with the condition progression in TG2576 mice

Supplementary MaterialsFIGURE S1: Olfactory -Amyloid pathology increases with the condition progression in TG2576 mice. layer; GrL: granular layer; AON: anterior olfactory nucleus). Presentation_1.PPTX (9.8M) GUID:?745D830E-FD14-4652-980A-22EE41C1AB38 FIGURE S2: OB PP5 up-regulation in 6-month-old Tg2576 mice (** 0.01 respect to control group) (A). No significant changes were found in FAK and PDK1/PKC signaling axis (B). Presentation_1.PPTX (9.8M) GUID:?745D830E-FD14-4652-980A-22EE41C1AB38 FIGURE S3: Visualization of predictive interactions Rabbit polyclonal to KCNV2 between APP and survival kinases (orange circles) based on differential datasets derived from 2-month-old Tg2576 mice. Presentation_1.PPTX (9.8M) GUID:?745D830E-FD14-4652-980A-22EE41C1AB38 FIGURE S4: Immunohistochemical localization of OB SEK1 and PKA (phosphorylated and non-phosphorylated forms). Representative immunohistochemical staining pattern of pSEK1 (A,B), SEK1 (C,D), pPKA (E,F) and PKA (G,H) in control and AD cases. Presentation_1.PPTX (9.8M) GUID:?745D830E-FD14-4652-980A-22EE41C1AB38 TABLE S1: Differential OB transcriptome in 2- and 6-month-old Tg2576 mice respect to WT mice. Table_1.xlsx (5.7M) GUID:?4B3C5F9F-A5D3-40A0-9DA2-BA0BE66EA8B2 TABLE S2: Diffefrential OB proteome in 2- and 6-month-old Th2576 mice respect to WT mice. Table_2.xlsx (26K) GUID:?AF7B6382-B2EA-4F87-A528-88055C05BB51 TABLE S3: Functional analysis of omics datasets. Table_3.xls (66K) GUID:?666A745B-0216-4499-B450-D7E82A71D925 Abstract The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimers disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques 2C-C HCl (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/ stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in 2C-C HCl transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD topics with different neuropathological grading. Used collectively, our data reveal the early effect of mutated APP for the OB molecular homeostasis, highlighting the intensifying modulation of particular signaling pathways through the olfactory amyloidogenic pathology. = 4C5/group). Five instances from elderly topics with no background or histological results of any neurological 2C-C HCl disease had been used like a control group. Eighty-five percentage of human being brains considered with this research got a post-mortem period (PMI) less than 15 h (Desk 1). Desk 1 General characteristics from the subject matter one of them scholarly research. with a typical rodent pellet diet plan (Global Diet plan 2014; Harlan Laboratories, Indianapolis, IN, USA) and got free usage of filtered and UV-irradiated drinking water. All pet care and experimental methods were relative to Spanish and Western regulations (86/609/CEE; RD1201/2005) and had been authorized by the Honest Committee from the College or university of Navarra (no. 018/05). Twenty-four pets, split into two models, were useful for proteomics and transcriptomics evaluation (12 mice/strategy), with at least three WT and three Tg2576 transgenic mice per stage (2- and 6-month-old). Additionally, 14- and 18-month-old pets had been useful for immunohistochemistry and cell success routes signaling evaluation. Table 3 summarizes 2C-C HCl the number and the purpose for each of the animals. The progressive development of AD signs in our colony has been previously described (Cuadrado-Tejedor and Garca-Osta, 2014). We have previously observed that behavior (Morris Water Maze test, MWM) is completely normal and amyloid levels are equal to wild type at 2 months of age. At 6 months of age, mice show impaired cognitive functions in the contextual fear conditioning test, 2C-C HCl coinciding with the increased cortical and hippocampal soluble amyloid (A) levels. At 12 months, the impairment in MWM is present in most of the mice, but few are normal and with less plaques (but they are present); and finally, in aged mice (17C18 months), the pathology is robust and 100% of mice shows plaques and MWM impairment. Table.