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Jun 21, 2021 / Neuroscience

Fighting Alzheimer’s disease with single cell research: Understanding selective neuronal vulnerability

Leida Tirado-Lee

To honor Alzheimer’s and Brain Awareness Month in June, we highlight a research publication investigating the molecular mechanisms contributing to selective neuronal vulnerability using 10x Genomics Single Cell Gene Expression (1). By defining the biomolecules that increase the susceptibility of neurons to degeneration, new therapeutic targets that may treat Alzheimer’s disease and related dementias can be explored.

Patients with Alzheimer’s disease slowly lose memories and cognitive skills in part due to neuronal degeneration and death. Credit: wildpixel, iStock / Getty Images Plus
Patients with Alzheimer’s disease slowly lose memories and cognitive skills in part due to neuronal degeneration and death. Credit: wildpixel, iStock / Getty Images Plus

Watching someone you love lose their precious memories, independence, and sense of self as Alzheimer’s disease (AD) claims their mind is heartbreaking. With over 50 million people worldwide living with Alzheimer’s disease and related dementias (ADRD), these diseases impact the lives of countless individuals, some we may know personally (1).

Currently, there is only one FDA-approved drug cited as potentially delaying clinical decline (2), and many other potential treatments have failed (3). However, there is still hope to improve outcomes for current and future patients. That hope is fueled, in part, by researchers who have dedicated their lives to understanding the mechanisms that contribute to ADRD development and progression so that we can better treat, or one day even prevent, these diseases.  

We have understood for some time that the APOE gene plays a role in AD risk. The APOE ε4 allele, in particular, is associated with an increased risk of AD development and earlier disease onset (4). We also know that some neurons, such as hippocampal neurons, are more vulnerable to neurodegeneration than others (5). A recent study published in Nature Neuroscience from Dr. Yadong Huang’s laboratory (Gladstone Institutes) has found a correlation between ApoE expression and neurodegeneration (6).  

A perfect fit for single cell sequencing

The fact that specific neurons are more vulnerable to neurodegeneration and that, even within this susceptible subset, the timeline of degeneration varies, highlights the need to look at each cell individually to find the root cause. Zalocusky et al. did just that, performing single nuclei sequencing (snRNA-seq) on hippocampi isolated from female mice with human ApoE knocked-in at four different time points (6). From a total of 123,489 nuclei in the dataset, 16 distinct neuronal clusters were identified after comparing the data against several publicly available datasets.

Image of a healthy neuron. Credit: National Institute on Aging, National Institutes of Health
Image of a healthy neuron. Credit: National Institute on Aging, National Institutes of Health

Within the neuronal cells identified, the researchers sought to show how ApoE expression varied from cell to cell. ApoE expression levels did account for a significant percentage of cell-to-cell variability in many neuronal populations, including dentate gyrus granule cells (73%) and CA1 pyramidal cells (82%). 

One key observation from the study is that the proportion of cells highly expressing ApoE changes in a way that correlates with disease progression. Specifically, in ApoE4-KI mice, the proportion of ApoE-expression-high cells peaks at around 15 months before declining, which is also the age at which neuronal and behavioral deficits begin. Similarly, in the human snRNA-seq dataset, ApoE-expression-high cells were most abundant in patients with mild cognitive impairment (MCI) but declined in patients with AD. Thus, the data indicate a potential role for ApoE expression early in disease development.

Dissecting the role of ApoE in selective vulnerability

The researchers examined which pathways were impacted by the variable ApoE expression. Interestingly, the top ApoE-correlated pathways were associated with cellular stress and immune response. The authors noted that while immune pathways have been of interest to the ADRD community, their connection to neuronal ApoE was previously unknown. Importantly, ApoE expression levels in human neurons were observed to have had similar effects on within-cell variation and impacted similar downstream pathways when examined in an snRNA-seq dataset generated from human patients with Alzheimer’s or MCI. This suggests that their findings are likely to translate to human patients. 

When looking at specific genes within the immune response pathways, it was found that major histocompatibility complex (MHC) genes showed a particularly strong association with the cell-to-cell ApoE expression levels. To investigate this further, the researchers performed snRNA-seq on ApoE-KI mice that had human ApoE expression eliminated in neurons. These neurons were found to have reduced levels of many MHC-I genes, suggesting that neuronal ApoE expression does indeed drive neuronal MHC gene expression. 

Using several functional methods, the authors went on to show that reducing the expression of MHC-I genes led to reduced features of tau pathology, such as p-tau mislocalization. In an interview with the Gladstone Institutes, Dr. Huang noted it is likely that, in the healthy brain, damaged neurons may use ApoE expression to turn on MHC-I genes and mark themselves for destruction (7). However, this process is likely dysregulated in Alzheimer’s disease leading to an increased loss of vulnerable neurons. 

Expanding the target pool for AD treatments

What do these findings mean for ADRD research moving forward? With the limited treatment options available today, finding new therapeutic targets is crucial to developing better treatments. As the authors note,

“This study...provides potential new targets for developing drugs to prevent or treat selective neurodegeneration in AD, such as lowering/blocking neuronal expression of ApoE, disconnecting the ApoE–MHC-I axis in neurons, inhibiting the machinery of MHC-I induction of tau pathologies or blocking MHC-I presentation of neurons to immune effector cells.” 

Deciphering the intricate pathologies of neurodegenerative diseases requires innovation, commitment, and support. At 10x Genomics, we provide single cell, spatial, and in situ products that help build a complete picture of complex biological systems in multiple dimensions. Learn more →

Lastly, in honor of Alzheimer’s and Brain Awareness Month, we’d like to thank Dr. Huang’s laboratory as well as the community of researchers who are improving the way we understand, diagnose, and ultimately treat Alzheimer’s and other neurodegenerative diseases.

References

  1. Alzheimer's Association. Alzheimer's Is a Global Epidemic. The Longest Day. https://act.alz.org/site/TR?fr_id=14244&pg=informational&sid=24694
  2. Alzheimer's Association. Treatments and Research. Alzheimer's Association. https://www.alz.org/help-support/i-have-alz/treatments-research
  3. Advisory Board. (2020, February 12). 'Crushing': Another Alzheimer's treatment trial has failed. What's next? Advisory Board. https://www.advisory.com/daily-briefing/2020/02/12/alzheimers-disease.  
  4. U.S. Department of Health and Human Services. (2019, December 24). Alzheimer's Disease Genetics Fact Sheet. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet.
  5. Mattson MP, Guthrie PB, and Kater SB. Intrinsic factors in the selective vulnerability of hippocampal pyramidal neurons. Prog Clin Biol Res 317: 333–51, 1989.
  6. Zalocusky KA, et al. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease. Nat Neurosci 24: 786–798, 202. doi: 10.1038/s41593-021-00851-3
  7. Stanley, S. (2021, May 6). Why Do Some Neurons Degenerate and Die in Alzheimer's Disease, but Not Others? Gladstone Institutes. https://gladstone.org/news/why-do-some-neurons-degenerate-and-die-alzheimers-disease-not-others.