Amelioration of Tau and ApoE4-linked glial lipid . . . - ALZFORUM Here, Alexandra Litvinchuk from David Holtzman’s laboratory investigated the effect of the LXR agonist GW3965 as well as overexpression of ABCA1 on tau and apoE4-linked glial lipid accumulation and neurodegeneration
Regulation of cell distancing in peri-plaque glial nets by . . . - ALZFORUM Important features of signaling within the glial nets—e g , the identity of the Plexin-B1 ligand, how Plexin-B1 activation in astrocytes affects the physiology of microglia—remain to be determined Nonetheless, pharmacological perturbation of Plexin-B1 signaling—not addressed in this study—could be experimentally assessed as an AD therapy
Glial lipid droplets resolve ROS during sleep. | ALZFORUM Most previous work on this process focused on disease conditions However, Haynes and colleagues discovered that glial lipid droplet accumulation occurs as part of a daily rhythm: in flies, glia accumulate lipid droplets during the day in response to normal neuronal activity, which are then metabolized by glial mitochondria at night during sleep
MAPT K317N | ALZFORUM Findings This mutation was detected in a woman with a constellation of symptoms suggestive of frontotemporal dementia, progressive supranuclear palsy, and motor neuron disease (Tacik et al , 2015) Her disease was categorized as globular glial tauopathy (GGT), a rare four-repeat tauopathy characterized by tau inclusions in astrocytes and oligodendrocytes (Ahmed et al , 2011)
APOE3Ch knock-in, floxed (CureAlz) x APPPS1 | ALZFORUM The Christchurch mutation, when homozygous, fully protected against these effects of APOE4 and showed a gene-dose-dependent effect on proportions of populations of neural cells identified through transcriptomic analyses—increasing disease-protective neuronal and glial subpopulations and decreasing disease-associated glial subpopulations ApoeCh
Transcriptomics Paint Astrocytes as Source of Cognitive Resilience Glial cells responded more consistently across regions, and the researchers pegged astrocytes as the lone cell type in which gene expression synced strongly with cognitive resilience Specifically, they cranked up production of polyamines and choline, two neuroprotective molecules
While a Fly Sleeps, Its Glia Burn Neuronal Lipids to Refresh the Brain . . . Further, neuronal but not glial mitochondria became oxidized This suggests that neurons were indeed the source of the peroxidated lipids and that, by shuttling them to glia, neurons protected their own mitochondria from oxidative stress To test this idea, Haynes knocked down neuronal Drp1, an ROS-activated mitochondrial damage response protein
“iAssembloids” Probe Glial Roles in Neuron Survival Interestingly, they discovered that this axis is undetectable in 2D or even 3D neuron monoculture models, highlighting the need for more sophisticated models replicating physiological neural-glial networks Notably, they detected and validated that a voltage-gated calcium channel beta subunit plays a role in APOE4 astrocyte-iAssembloids
Do APOE4’s Lipid Shenanigans Trigger Tauopathy? - ALZFORUM Meanwhile, work from multiple groups had shown that APOE4 perturbs lipid metabolism in glial cells, spurring inflammation and amyloidosis (Apr 2019 conference news; Nov 2021 conference news) Fatty Buildup In microglia (red), lysosomes (purple) fill up with cholesterol esters (green) in tauopathy mice expressing APOE4 (right), but not APOE3
DNL788 - ALZFORUM These and other studies raised the profile of RIPK1 as a glial target to try to reduce neuroinflammation and cell death across several neurodegenerative diseases (Yuan et al , 2019)