Not surprisingly, neurons and microglia are both impacted by the degenerative changes that are associated with brain disorders, like Alzheimer’s disease. But, how those manifestations differ between the two cell types, is not well understood. How microglia are affected remains particularly understudied. Shedding light on these questions would have important implications for Alzheimer’s disease research.
Jessica Young, PhD is an associate professor of Lab Medicine and Pathology and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). Her lab uses induced pluripotent stem cells (iPSC) to explore how operational breakdowns within neurons and microglia contribute to Alzheimer’s disease.
In particular, the Young Lab is interested in the dysfunction along the endo-lysosomal pathway that can occur over many years.
Endosomes are intra-cellular sorters and couriers. Like members of a mailroom staff, they deliver incoming packages to wherever they need to go within the cell and handle outgoing shipments as well. They also transport old or broken cell components to the lysosome for degradation. The Young Lab believes disruptions to these processes cause protein traffic jams that can lead to Alzheimer’s disease.
In previous studies, the team studied neurons that had loss of a gene called SORL1, which encodes a protein called SORLA. The SORL1 gene has recently been strongly genetically associated with increased risk for Alzheimer’s disease. In these SORL1-deficient neurons, endosomes were unable to sort proteins correctly, leading to enlargement of the organelles and decreased lysosomal function.
When this happens in Alzheimer’s disease, essential proteins are not trafficked properly, waste piles up, and brain power is diminished. In the Young Lab’s research, some of the proteins that were building up in the endosomes were the amyloid precursor protein, which generates amyloid beta, and proteins involved in synaptic function.
“All this junk is building up in the cell. If amyloid beta is not being fully degraded, for example, that’s a problem. It can also affect the immune response. If microglia begin pruning the synapse of neurons too aggressively, that’s going to contribute to neurodegeneration.”
The observations in microglia differed. There were fewer endosomal traffic jams, but, as with neurons, the lysosomes seemed to lose their ability to break down toxic molecules. How exactly these problems unfold in microglia is the focus of a new study, published in the journal GLIA, that could aid in the design of therapies to address the underlying causes of neurodegeneration before they become irreversible.
Dr. Young is the senior author of the paper. Swati Mishra, PhD, an Acting Instructor in the Young Lab, is the first author. ISCRM faculty member Sumie Jayadev, MD, is also an author of the study.
In the investigation, the researchers used CRISPR gene-editing to knockout SORL1/SORLA in microglia. They found that microglia still take threat assessment seriously. The glia carry on rounding up substances, like bacteria or toxic proteins, as part of their immune response duties. However, the enzymes that are responsible for degradation are not being delivered to the lysosome.
The result? Harmful junk accumulates inside the cell, which leads to stress. Young says their hypothesis is that this gradual build up can eventually throw the brain’s immune system off kilter. The initial response to a threat could be blunted, or the microglia could begin cleaning house too aggressively, triggering harmful neuroinflammation, which could include attacking healthy synapses.
The bottom line, says Dr. Mishra, is a clearer understanding of the effects a loss of SORL1/SORLA have on microglia. “This research demonstrates that lack of SORLA causes dysfunction of lysosomes in human microglia and our conclusion from this paper is that dysfunction of the lysosomal pathway in microglia is potentially a key pathogenic mechanism in Alzheimer’s disease.”
Mishra recently received independent funding to continue the investigation. An Alzheimer’s Association Research Fellow grant will allow her to use AD patient cells to identify dysfunctional lysosomal pathways in microglia that can be targeted at early stages of the disease.
Young echoes the translational motivation behind the research. “If you’re thinking about designing a therapeutic, you have to understand the differences between cell types because every cell in the brain will be exposed to that drug. That’s why we think these studies are important to do before we start treating people.”
Acknowledgement:
This study was supported by NIA R01 AG062148, R01 AG AG080585 and an Alzheimer’s Association Grant 23AARG-1022491 to J.E.Y., a Development Award to SM from the UW ADRC P30 AG066509, Alzheimer’s Association “Endolysosomal Defects and Neuron-glia Crosstalk in Neurodegenerative Diseases” grant to B.S., and NIH training grants 5T32AG222-30 and 1F32AG079666-01 to N.M.