Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model.

Microglia help limit the progression of Alzheimer's disease (AD) by constraining amyloid-ß (Aß) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aß and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aß plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aß load, mitigated some Aß-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

Pneumatically Sprayed Gold Nanoparticles for Mass Spectrometry Imaging of Neurotransmitters.

Using citrate-capped gold nanoparticles (AuNPs) for laser desorption ionization mass spectrometry (LDI-MS) is an approach that has demonstrated broad applicability to ionization of different classes of molecules. Here, we show a simple AuNP-based approach for the ionization of neurotransmitters. Specifically, the detection of acetylcholine, dopamine, epinephrine, glutamine, 4-aminobutyric acid, norepinephrine, octopamine, and serotonin was achieved at physiologically relevant concentrations in serum and homogenized tissue. Additionally, pneumatic spraying of AuNPs onto tissue sections facilitated mass spectrometry imaging (MSI) of rabbit brain tissue sections, zebrafish embryos, and neuroblastoma cells for several neurotransmitters simultaneously using this quick and simple sample preparation. AuNP LDI-MS achieved mapping of neurotransmitters in fine structures of zebrafish embryos and neuroblastoma cells at a lateral spatial resolution of 5 µm. The use of AuNPs to ionize small aminergic neurotransmitters in situ provides a fast, high-spatial resolution method for simultaneous detection of a class of molecules that typically evade comprehensive detection with traditional matrixes.