Investigators at the Weizmann Institute of Science have identified changes in oligodendrocytes that were shared across multiple dementia types. The team reported its results in the June 27, 2022, online issue of Nature Neuroscience.
The team originally identified the cells, which they called disease-associated oligodendrocytes (DOLs), in a mouse model of Alzheimer's disease (AD), and initially suspected their signature might be a result of exposure to amyloid plaques.
But although DOLs tended to be located near plaques in the postmortem brains of patients with AD, the team also identified them in animal models of other neurodegenerative and autoimmune inflammatory disorders. And in cell culture experiments, exposure to amyloid-beta was not enough to induce the signature. The authors wrote in their papers that the presence of DOLs "in brain areas enriched with plaques suggests an involvement of additional factors, such as damage-associated molecular patterns (DAMPs), the release of various metabolic factors from dying cells and inflammation."
Amyloid plaques are the anatomical hallmark of AD, and targeting them has consumed the lion's share of attention as far as the biopharma industry is concerned.
It is a strategy that has led to dozens of failed clinical trials, and so far, a single FDA-approved agent – Aduhelm (aducanumab, Biogenm Inc.) – whose approval was more than controversial and whose sales have lagged accordingly.
Even if other amyloid-targeting agents with clearer evidence of benefit ever come along, what is abundantly clear already is that such agents will have to be used very early in the disease, long before the onset of clinically relevant symptoms, to alter the disease course.
Meanwhile, there are myriad changes in AD beyond the accumulation of amyloid plaque. Those changes affect multiple cell types besides neurons. And although AD is the most common one, it is only one of many neurodegenerative diseases.
The lab of Michal Schwartz, who is a professor of neuroimmunology at the Weizmann Institute and co-senior author on the paper reporting the new findings, has previously reported on the role that immune cells such as microglia play in neurodegenerative diseases. In their new experiments, the team used single-cell RNA sequencing to gain a deeper understanding of how other cell types besides neurons might be affected by disease.
The team compared the transcriptomes of multiple cell types from genetically normal animals to those from a mouse model of AD caused by overproduction of beta-amyloid. They found that oligodendrocytes, which make up 20% of all brain cells, showed the largest differences in gene expression between AD animals and controls.
Further experiments showed that the same oligodendrocyte changes occurred in models where AD is not driven by amyloid beta, and even in non-Alzheimer's neurodegeneration models. Two previously published sets of data from animals with experimental autoimmune encephalitis, the closest animal model to multiple sclerosis, showed similar changes. The team wrote in their paper that "our meta-analysis further substantiated the notion that the DOL response is a conserved response of oligodendrocytes to pathological deviation from CNS homeostasis, which might be relevant to multiple diseases beyond AD."
The strongest difference between normal and AD mice was in the expression of SerpinA3N, and the team showed that those changes were mirrored in the postmortem brains of patients with AD. Understanding whether pharmacological targeting of the changes would be a useful strategy in AD or other forms of neurodegeneration will require follow-up studies. But the authors concluded that as a first step, "our work shows the common molecular pathways that oligodendrocytes acquire in different neurodegenerative conditions and highlights the potential of targeting these common pathological mechanisms underlying [central nervous system] diseases."