DOI: 10.5061/dryad.51c59zwdv
title: Leukotriene A4 hydrolase inhibition improves age related cognitive decline via modulation of synaptic function (Part 2/2)

description: Leukotrienes, a class of inflammatory bioactive lipids, are well studied
 in the periphery but less is known of their importance in the brain. We
 identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed
 in healthy mouse neurons, and inhibition of LTA4H in aged mice improves
 hippocampal dependent memory. Single cell nuclear RNA sequencing of
 hippocampal neurons after inhibition reveals major changes to genes
 important for synaptic organization, structure, and activity. We propose
 that LTA4H inhibition may act to improve cognition by directly inhibiting
 the enzymatic activity in neurons leading to improved synaptic function.
 Additionally, LTA4H plasma levels are increased in both aging and
 Alzheimer’s disease and correlated with cognitive impairment. These
 results identify a novel role for LTA4H in the brain and we propose that
 LTA4H inhibition may be a promising therapeutic strategy to treat
 cognitive decline in aging related diseases.
description: Aged mice were anesthetized two hours after final dosing using
 isoflurane and transcardially perfused with 20 mL ice-cold artificial
 cerebrospinal fluid. Hippocampi were micro-dissected from 3 mice per
 treatment group and processed for nuclei isolation for 10x Genomics single
 nuclei sequencing following manufacturer’s guidelines (10x Genomics Sample
 Preparation Demonstrated Protocol CG000124; 10x Genomics, Pleasanton, CA)
 with the following modification: lysis incubation time was increased to 4
 minutes. Nuclei were stained for NeuN using a PE-conjugated anti-NeuN
 antibody (EMD Millipore, FCMAB317PE, 1:1000) and counterstained with DRAQ5
 (Fisher Scientific, PI62251; 1:5,000) for 30min on ice to allow separation
 of nuclei from debris particles using a Sony MA900 FACS sorter (Sony
 Biotechnology, San Jose, CA). Eight samples of 8,000 nuclei each were
 collected per treatment group and immediately processed for 10x single
 nuclei sequencing using the 10x Genomics Chromium Next GEM Single Cell 3’
 Reagent Kits v3.1 Dual Index (CG000315 Rev B). Single nuclei libraries
 were sequenced on an Illumina NovaSeq 6000 to a target depth of ~50,000
 reads per cell.
description: The data repository contains raw sequencing
 data, using standard 10x genomics practices. Each sample consists of 8
 files (four index files and 2 sets of read pairs). This
 is one of two datasets related to the same study: Part
 1 contains 14 of the 24 total samples, https://datadryad.org/stash/dataset/doi:10.5061/dryad.fbg79cp1c.<br>Part 2 (this dataset) contains 10 of the 24 total samples, https://datadryad.org/stash/dataset/doi:10.5061/dryad.51c59zwdv. Supplied fastq files can be processed using 10x Genomics cell ranger and subsequently can be opened using open source R packages, such as Seurat or SCE.
description: # Leukotriene A4 hydrolase inhibition improves age related cognitive
 decline via modulation of synaptic function (Part 2)
 [https://doi.org/10.5061/dryad.51c59zwdv](https://doi.org/10.5061/dryad.51c59zwdv) Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons leading to improved synaptic function. Additionally, LTA4H plasma levels are increased in both aging and Alzheimer's disease and correlated with cognitive impairment. These results identify a novel role for LTA4H in the brain and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases. ## Description of the Data and file structure Data repository contains raw sequencing data, using standard 10x genomics practices. This is one of two datasets related to the same study: Part 1 contains 14 of the 24 total samples, https://datadryad.org/stash/dataset/doi:10.5061/dryad.fbg79cp1c. Part 2 (this dataset) contains 10 of the 24 total samples, https://datadryad.org/stash/dataset/doi:10.5061/dryad.51c59zwdv. Each sample follows the naming convention FACSYYYY-MM-DD_n where YYYY-MM-DD indicates the date of the experiment and n indicates the tube number for that sample. Each sample has 8 files associated with it, four index files and 2 sets of read pairs. Was data derived from another source? If yes, list source(s): n/a