Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease.

Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation.

Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease.

Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD.

One Scaffold, Different Organelle Sensors: pH-Activable Fluorescent Probes for Targeting Live Microglial Cell Organelles.

Targeting live cell organelles is essential for imaging, understanding, and controlling specific biochemical processes. Typically, fluorescent probes with distinct structural scaffolds are used to target specific cell organelles. Here, we have designed a modular one-step synthetic strategy using a common reaction intermediate to develop new lysosomal, mitochondrial, and nucleus-targeting pH-activable fluorescent probes that are all based on a single boron dipyrromethane scaffold.

Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time.

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown.

Accelerated Reactivity Mechanism and Interpretable Machine Learning Model of -Sulfonylimines toward Fast Multicomponent Reactions.

We introduce chemical reactivity flowcharts to help chemists interpret reaction outcomes using statistically robust machine learning models trained on a small number of reactions. We developed fast sulfonylimine multicomponent reactions for understanding reactivity and to generate training data. Accelerated reactivity mechanisms were investigated using density functional theory.

Spectral deep learning for prediction and prospective validation of functional groups.

State-of-the-art identification of the functional groups present in an unknown chemical entity requires the expertise of a skilled spectroscopist to analyse and interpret Fourier transform infra-red (FTIR), mass spectroscopy (MS) and/or nuclear magnetic resonance (NMR) data. This process can be time-consuming and error-prone, especially for complex chemical entities that are poorly characterised in the literature, or inefficient to use with synthetic robots producing molecules at an accelerated rate. Herein, we introduce a fast, multi-label deep neural network for accurately identifying all the functional groups of unknown compounds using a combination of FTIR and MS spectra.

Rapid, Refined, and Robust Method for Expression, Purification, and Characterization of Recombinant Human Amyloid beta 1-42.

Amyloid plaques found in the brains of Alzheimer's disease patients primarily consists of amyloid beta 1-42 (Aβ42). Commercially, Aβ42 is synthesized using high-throughput peptide synthesizers resulting in the presence of impurities and the racemization of amino acids that affects its aggregation properties. Furthermore, the repeated purchase of even a small quantity (~1 mg) of commercial Aβ42 can be expensive for academic researchers.

Access to Imidazolidine-Fused Sulfamidates and Sulfamides Bearing a Quaternary Center via 1,3-Dipolar Cycloaddition of Nonstabilized Azomethine Ylides.

A 1,3-dipolar cycloaddition reaction of nonstabilized azomethine ylides and cyclic N-sulfonyl imines has been developed providing a workable access to imidazolidine-fused sulfamidates, sulfamides, and benzosultams bearing a quaternary center. Distinct from the available literature, this current work enables to make entry, for the first time, into the novel imidazolidine-fused sulfamidates and sulfamides. Furthermore, the selective imidazolidine ring opening accompanied by CH extrusion yielded tetra-substituted sulfamidates with an aminomethyl group.

Intramolecular Acylation of Unactivated Pyridines or Arenes via Multiple C-H Functionalizations: Synthesis of All Four Azafluorenones and Fluorenones.

An unprecedented intramolecular acylation of unactivated pyridines via multiple C(sp/sp)-H functionalizations of a methyl, hydroxymethyl, or aldehyde group has been developed providing a general access to all four azafluorenones. The application of this protocol is further demonstrated to the synthesis of azafluorenone related fused nitrogen heterocycles and fluorenones. In addition, design and synthesis of a novel fluorene based organic emitter for potential use in organic light emitting devices (OLEDs) is also reported.

Implications of dynamic imine chemistry for the sustainable synthesis of nitrogen heterocycles via transimination followed by intramolecular cyclisation.

An exploration of a tandem approach to the sustainable synthesis of N-heterocycles from readily available N-aryl benzylamines or imines and ortho-substituted anilines is described, which demonstrates, for the first time, an important synthetic application of dynamic imine chemistry. The key features to the successful development of this protocol include the utilisation of N-aryl benzylamines as imine precursors in transimination, the occurrence of transimination in acetonitrile in the absence of any catalysts, an intramolecular nucleophilic addition occurring in the newly formed imine causing irreversible transimination, and the tandem event occurring under green conditions.

Scope of Successive C-H Functionalizations of the Methyl Group in 3-Picolines: Intramolecular Carbonylation of Arenes to the Metal-Free Synthesis of 4-Azafluorenones.

A transition-metal-free, t-BuOOH mediated intramolecular carbonylation of arenes in 2-aryl-3-picolines via oxidative C-H functionalizations of the methyl group has been developed, providing an expedient synthesis of 4-azafluorenones. Distinct from the current literature wherein methylarenes have been used as acylating agents, 2-aryl-3-picolines in this study are transformed into aldehydes, which give 4-azafluorenones upon rapid intramolecular acylation. The study demonstrates the first example of intramolecular carbonylation of arenes utilizing a methyl group as latent carbonyl functionality.

Access to biaryl sulfonamides by palladium-catalyzed intramolecular oxidative coupling and subsequent nucleophilic ring opening of heterobiaryl sultams with amines.

The installation of sulfonamide pharmacophores on heterobiaryls has successfully been executed by a previously unknown palladium-catalyzed intramolecular oxidative coupling in N-arylsulfonyl heterocycles followed by novel ring opening of heterobiaryl sultams with amine nucleophiles. The protocol has a wide scope of substrates warranting broad applications in the synthesis of heterobiaryls containing an o-sulfonyl or carboxyl functional group.

Palladium-catalyzed intramolecular oxidative coupling involving double C(sp(2))-H bonds for the synthesis of annulated biaryl sultams.

The palladium-catalyzed intramolecular oxidative coupling described herein involves a double C(sp(2))-H bond functionalization in sulfonanilides, providing a workable access to biaryl sultams annulated into a six-membered ring that are otherwise difficult to obtain by literature methods. The other synthetic applications of this protocol including the synthesis of biaryl sultams containing a seven-membered ring and analogous sultones are also presented.

Palladium-catalyzed regio- and chemoselective ortho-benzylation of C-H bond using a functionalizable primary amide directing group: a concise synthesis of dibenzo[b,e]azepin-6-ones.

A palladium-catalyzed regio- and chemoselective direct benzylation of primary benzamides with 2-bromobenzyl bromides under a mild basic condition has been developed affording various substituted diarylmethanes in good yields. Furthermore, the directing amide group (-CONH2) was subjected to intramolecular N-arylation with the aryl bromide moiety present in diarylmethanes leading to a concise synthesis of dibenzoazepinones.