Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome.

Background: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear.

Improvement for a full-spectrum modulated nonlinear frequency division multiplexing transmission system.

Nonlinear frequency division multiplexing (NFDM), as a possible technique to overcome the limit imposed by Kerr nonlinearity in conventional coherent optical communication systems, has attracted widespread attention in the communication community in recent years. In order to fully utilize the available degrees of freedom in the nonlinear spectrum, this paper focuses on the full-spectrum (FS) modulated NFDM system. First, we maximize the data rate of discrete spectrum (DS) by optimizing the distribution of eigenvalues in DS part of FS.

Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia.

We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes.

Narrow- or wide-band channel for a high baud rate fiber communication system: a judgment based on a temporal and spectral evolution PMD model.

In optical fiber communication systems, the tendency to prefer increasingly higher baud rates, up to 100 or 200 Gbaud, compels us to deal with wideband fiber channels in which polarization effects must be treated in a more complicated manner. In contrast to the conventional 50 GHz bandwidth wavelength division multiplexing channel, polarization mode dispersion (PMD) is observed in an all-order manner in a wideband fiber channel beyond 100 GHz, rather than only first- and second-order. In this study, certain principles that should be followed in establishing a PMD emulation model in a wideband fiber channel were put forward.

Nonlinear frequency domain PMD modeling and equalization for nonlinear frequency division multiplexing transmission.

Polarization mode dispersion (PMD) is one of the fundamental properties of a standard single-mode fiber. It affects the propagating signals and degrades the performance of high-speed optical fiber communication systems. PMD also gives an effect on the nonlinear spectra or scattering data in nonlinear frequency division multiplexing (NFDM) systems.

Probabilistic shaping and neural network-based optimization for a nonlinear frequency division multiplexing system.

A joint scheme introducing probabilistic shaping (PS) at the transmitter and utilizing a neural network (NN) equalizer at the receiver is proposed to improve the performance of the -modulated nonlinear frequency division multiplexing (NFDM) system. Through a numerical simulation, we demonstrate that PS plays a leading role for low launch power case, which improves the performance of the system effectively, while the NN equalizer's superiority appears in a high launch power region, whose main role is to weaken the correlation among subcarriers for improving system performance. The proposed scheme would enlighten the optimum modulation and detection schemes of the NFDM system.

An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo.

Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Aβ peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated.

Robust neural network receiver for multiple-eigenvalue modulated nonlinear frequency division multiplexing system.

Nonlinear frequency division multiplexing (NFDM) has been shown to be promising in overcoming the fiber Kerr nonlinearity limit. In multiple-eigenvalue modulated NFDM systems, the transmission capacity increases with the number of modulated eigenvalues. However, as the number of modulated eigenvalues increases, the complexities of the signal waveform and the nonlinear Fourier transform (NFT) algorithm for demodulation increase dramatically as well, while the accuracy drops significantly.

Nonlinear-frequency-packing nonlinear frequency division multiplexing transmission.

A nonlinear frequency division multiplexing (NFDM) transmission system, designed specifically for nonlinear fiber channel, has the potential to overcome the nonlinear Shannon capacity limit. However, the spectral efficiency (SE) of the current proven NFDM transmission systems is still lower than that of the analogous orthogonal frequency division multiplexing system. It is extremely necessary to explore effective modulation scheme for the aim of increasing the SE of NFDM system.

Negative evidence for a role of APH1B T27I variant in Alzheimer's disease.

γ-secretase is a macromolecular complex that catalyzes intramembranous hydrolysis of more than 100 membrane-bound substrates. The complex is composed of presenilin (PS1 or PS2), anterior pharynx defect-1 (APH-1), nicastrin (NCT) and PEN-2 and early-onset; autosomal dominant forms of Alzheimer's disease (AD) are caused by inheritance of mutations of PS. No mutations in genes encoding NCT, or PEN-2 have been identified to date that cause AD.

Frequency offset estimation for nonlinear frequency division multiplexing with discrete spectrum modulation.

Although fruitful studies have been conducted on carrier frequency offset (CFO) estimations in linear coherent optical fiber communication systems, there are few studies on CFO estimations and recoveries in the systems based on the nonlinear Fourier transform (NFT). Although the CFO is originated from the linear frequency domain, it definitely has effects on nonlinear spectra, including the shift of the nonlinear frequency and the phase rotations of the scattering data, which are similar to its effects on linear spectra. This work indicates that it is feasible to estimate frequency offset (FO) by capturing symbol variations in the nonlinear frequency domain (NFD) rather than in the linear frequency domain; the latter was usually exploited in the literature.

Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes.

We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein ( /presenilin 1 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive (APPPS1-21) mouse model of Aβ amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aβ pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice.

Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity.

Understanding of the structure of the γ-secretase complex consisting of presenilin (PS), anterior pharynx-defective 1 (APH-1), nicastrin (NCT), and presenilin enhancer 2 (PEN-2) is of significant therapeutic interest for the design of γ-secretase modulators for Alzheimer disease. The structure of γ-secretase revealed by cryo-EM approaches suggested a substrate binding mechanism for NCT, a bilobar structure that involved rotation of the two lobes around a central pivot and opening of a "lid" region that facilitates substrate recruitment. To validate this proposal, we expressed NCT that lacks the lid entirely, or a variety of NCT variants that harbor mutations at highly conserved residues in the lid region inNCT-deficient cells, and then assessed their impact on γ-secretase assembly, activity, and stability.

The topology of pen-2, a γ-secretase subunit, revisited: evidence for a reentrant loop and a single pass transmembrane domain.

Background: The γ-secretase complex, composed of transmembrane proteins termed presenilin (PS), anterior pharynx defective (APH), nicastrin (NCT), and presenilin enhancer-2 (Pen-2) catalyzes intramembranous hydrolysis of a variety of Type I membrane protein substrates. In order to understand aspects of subunit assembly, interactions, dynamics and catalysis, it is essential to clarify the membrane topology of each polypeptide. Hydophathicity plots predict that the 101 amino acid Pen-2 molecule has two hydrophobic domains (HP1 and HP2) that may serve as transmembrane spanning domains.

A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of γ-secretase.

The γ-secretase complex, composed of presenilin, nicastrin (NCT), anterior pharynx-defective 1 (APH-1), and presenilin enhancer 2 (PEN-2), is assembled in a highly regulated manner and catalyzes the intramembranous proteolysis of many type I membrane proteins, including Notch and amyloid precursor protein. The Notch family of receptors plays important roles in cell fate specification during development and in adult tissues, and aberrant hyperactive Notch signaling causes some forms of cancer. γ-Secretase-mediated processing of Notch at the cell surface results in the generation of the Notch intracellular domain, which associates with several transcriptional coactivators involved in nuclear signaling events.

Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species.

Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid β peptide variant (Aβ42). In the majority of familial AD (FAD) cases, e.g.

A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2.

Presenilins 1 and 2 (PS1 and PS2) are the catalytic subunits of the γ-secretase complex, and genes encoding mutant PS1 and PS2 variants cause familial forms of Alzheimer's disease. Lee et al. (2010) recently reported that loss of PS1 activity lead to impairments in autophagosomal function as a consequence of lysosomal alkalinization, caused by failed maturation of the proton translocating V0a1 subunit of the vacuolar (H+)-ATPase and targeting to the lysosome.

Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies.

The γ-secretase complex, composed of presenilin, anterior-pharynx-defective 1, nicastrin, and presenilin enhancer 2, catalyzes the intramembranous processing of a wide variety of type I membrane proteins, including amyloid precursor protein (APP) and Notch. Earlier studies have revealed that nicastrin, a type I membrane-anchored glycoprotein, plays a role in γ-secretase assembly and trafficking and has been proposed to bind substrates. To gain more insights regarding nicastrin structure and function, we generated a conformation-specific synthetic antibody and used it as a molecular probe to map functional domains within nicastrin ectodomain.

Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy.

The γ-secretase membrane protein complex is responsible for proteolytic maturation of signaling precursors and catalyzes the final step in the production of the amyloid β-peptides implicated in the pathogenesis of Alzheimer disease. The incorporation of PEN-2 (presenilin enhancer 2) into a pre-activation intermediate, composed of the catalytic subunit presenilin and the accessory proteins APH-1 (anterior pharynx-defective 1) and nicastrin, triggers the endoproteolysis of presenilin and results in an active tetrameric γ-secretase. We have determined the three-dimensional reconstruction of a mature and catalytically active γ-secretase using single-particle cryo-electron microscopy.

Activation and intrinsic gamma-secretase activity of presenilin 1.

A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for γ-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of γ-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits γ-secretase activity.

Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37).

3'UTR-dependent localization of a Purkinje cell messenger RNA in dendrites.

Pcp2(L7) is a Purkinje cell-specific GoLoco domain protein that modulates activation of Galphai/o proteins by G protein-coupled receptors. A likely downstream effector of this pathway is the P-type Ca(2+) channel, and thereby, the intrinsic electrophysiology of Purkinje cells could be modulated by Pcp2(L7). It has long been known that the Pcp2(L7) mRNA is abundantly localized in dendrites, suggesting the possibility of distal synthesis and local changes in levels of the protein.

Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.

Cerebral deposition of beta-amyloid (Abeta) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein gamma-secretase complex generates Abeta. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of gamma-secretase and that the levels of secreted Abeta inversely correlate with CD147 expression.