Researchers at the Max Planck Institute have utilised single cell and spatial genomics in their Nature paper to uncover a new perspective on how an aging brain leads to Alzheimer’s.
Alzheimer’s and the aging brain
It is well known that as we get older our risk of Alzheimer’s Disease increases, but why is this?
Lots of things change in the brain as we age. One of which is the progressive loss of the myelin sheath (part of the white matter) around neurons. The myelin sheath is the fatty layer around neurons, which insulates the electrical current to allow faster and more effective signaling in the brain.
When it comes to Alzheimer’s Disease, one clear issue in the brain is the accumulation of toxic amyloid plaques which damage brain cells. Naturally, researchers have principally studied how these toxic plaques may damage and weaken the myelin, progressing natural aging. However, the research cited here has flipped the script and investigated the opposite, implying that damage to myelin sheath is the instigator in worsening Alzheimer’s progression.
Flipping the script
The research covered here relied mostly on animal models of Alzheimer’s that were modified genetically to accumulate amyloid-plaques. However, by also removing genes essential for building the myelin sheath around neurons, the researchers were effectively able to create a mouse model to see how myelin dysfunction was associated with Alzheimer’s disease.
One of the lead authors, Ting Sung, reported that in their model, “the defective myelin stresses the nerve fibers causing them to swell and produce more Aꞵ peptides.” This means that age-related deterioration of the myelin sheath can promote amyloid plaque formation. This was not the only problem, though.
Mistargeting microglia
Amyloid naturally accumulates in our brains but the immune system, specifically the microglia, tirelessly clears amyloid away each day. In a fantastic use of single-cell and spatial biology, researchers here were able to find out that microglia were no longer principally responding to amyloid-plaques. In fact, they noted ‘an almost complete loss of plaque-corralling microglia’. Single-nuclei transcriptomics showed that a portion of microglia had upregulated genes for lipid metabolism. This strongly suggested that they were clearing the myelin debris instead of managing the amyloid plaques.
Overall, this model suggests that the immune cells that would typically remove plaques had a new target in the defective myelin and essentially become ‘distracted’ from the task in hand. The bottom line of this research is that slowing down age-related myelin damage could be a fruitful avenue for future Alzheimer’s treatment.
