There is emerging evidence that Alzheimer’s disease (AD) affects peripheral tissues as well as neuronal tissue, but studies focused on the impact of AD on peripheral tissue are limited. FunGen-AD researcher Hugo Bellen and a team headed by Hongjie Li at Baylor College of Medicine profiled the transcriptome of AD fly models to analyze the effects of expressing amyloid-β 42 peptide (Aβ42) and tau in neurons. The researchers expressed human versions of either Aβ42 or tau in adult fly neurons using a controllable gene expression system. The researchers then separated the heads and bodies of these flies at specified time points and analyzed transcriptional changes through single-nucleus RNA sequencing. They revealed systemic changes of 219 cell types across the whole organism.
Analysis of the results from the Aβ42 flies showed that the peptide causes neuronal damage in the central nervous system, with sensory neurons being the most susceptible. The researchers explored how Aβ42 caused neuron loss and identified a neuronal cell cluster with increased expression of lactate dehydrogenase (Ldh). Further analysis showed that this high Ldh expression neuron cluster has transcripts related to endoplasmic reticulum (ER) stress. The Ldh neuron cluster is also conserved in AD mouse models and human AD datasets. In contrast, flies with induced tau expression show altered gene expression in peripheral tissues. The greatest effects of tau on the periphery were on fat metabolism, digestion, and reproduction. Analysis of the lipid droplets in the tau flies’ fat stores showed an increased lipid droplet size early and reduced droplet size later. This indicates that tau expression leads to dysregulated lipid metabolism. Other analyses also show that flies with induced tau expression have dysregulated gut homeostasis. Overall, these experiments indicate that Aβ42 mostly affect the central nervous system and especially the neurons involved in processing peripheral input while tau affects peripheral organs and leads to premature aging.
This research, partially supported by FunGen-AD grant U01AG072439, is published in Neuron here. You can read more about these research findings at the following links:
- Alzheimer’s disease affects an organism as a whole (Baylor College of Medicine)
- Alzheimer’s Disease Affects Tissues Beyond the Brain (The Scientist)
- Alzheimer’s Disease Alters Body Organs, Not Just the Brain (Technology Networks)
- Alzheimer’s Disrupts the Whole body, Not Just the Brain (Neuroscience News)
- Fruit fly study links Alzheimer’s proteins to widespread organ changes and sensory decline (Medical Xpress)