Neuroprotective mechanism altered by Alzheimer's disease risk genes

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BrianR
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Neuroprotective mechanism altered by Alzheimer's disease risk genes

Post by BrianR »

Negatives: Paywalled paper & fruit fly APOE4 model. But an interesting lead if it bears out.

Science Daily explainer: https://www.sciencedaily.com/releases/2 ... 121721.htm
The brain has a natural protective mechanism against Alzheimer's disease, and researchers ... have discovered that gene variants [APOE4, etc] associated with risk of developing the disease disturb the protective mechanism in ways that can lead to neurodegeneration. The researchers also showed in a fruit fly model of the condition that a chemical known as ABCA1 agonist can restore certain alterations of the brain protective mechanism.

The team reveals evidence supporting reactive oxygen species (ROS), natural byproducts of cellular metabolism linked to inflammation and other processes, as key players in events leading to the disruption of the neuroprotective mechanism. In addition, the researchers found that ROS, together with amyloid-beta, the main component in the plaques found in the brains of people with Alzheimer's disease, accelerated disease development in animal models. ...

Paper: https://www.pnas.org/content/118/52/e2112095118
Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease–associated genes
Matthew J. Moulton, Scott Barish, Isha Ralhan, Jinlan Chang, Lindsey D. Goodman, Jake G. Harland, Paul C. Marcogliese, Jan O. Johansson, Maria S. Ioannou, and Hugo J. Bellen
PNAS December 28, 2021 118 (52) e2112095118;
DOI: 10.1073/pnas.2112095118
Significance
Multiple studies have implicated dozens of risk loci that may be associated with Alzheimer’s disease (AD), but common mechanisms underlying how they may contribute to disease onset or progression remain elusive. This study identifies cell-specific roles for Drosophila orthologs of AD risk genes in lipid droplet formation that, when disrupted, lead to neurodegeneration. Our work reinforces a critical role for the sequestration of peroxidated lipids in glia, and places Apolipoprotein E ε4 (APOE4) with other AD risk factors in the transfer process of lipids from neurons to glia to form lipid droplets.

Abstract
A growing list of Alzheimer’s disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induces lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent. To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP. Our data also show that ROS enhances Aβ42 phenotypes in flies and mice. Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.
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Brian4
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Re: Neuroprotective mechanism altered by Alzheimer's disease risk genes

Post by Brian4 »

The preprint is freely available here:

https://www.biorxiv.org/content/10.1101 ... 3.433580v1

These people are trying to bring this to market:

https://www.arterytx.com/

This looks like a very promising approach!

Brian
ε4/ε4 (for now).
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