Neuroscientists and stem cell researchers at Lund University in Sweden have developed a research model that studies human hippocampal neurons, the brain cells primarily affected by the pathology of Alzheimer’s disease. The study was published in Stem cell reports.
In Alzheimer’s disease, the hippocampus, a brain structure that regulates motivation, emotion, learning and memory, is severely affected.
However, due to the unavailability of hippocampal tissue, except post-mortem, it is not possible for researchers to understand what are the primary events that lead to cell dysfunction and subsequent neuronal damage.
Understanding which cell pathways are changed very early in Alzheimer’s disease would allow the development of therapies that could slow the disease.
Lund researchers successfully generated 3D hippocampal tissue structures from Induced pluripotent stem cells (iPSC), called hippocampal spheroids (HS). The spheroids are enriched with so-called granulated neurons.
In most vertebrate species, including humans, new granulated neurons are generated throughout life through a process called neurogenesis and are thought to contribute to memory formation.
The new method developed by the scientists will intensify the production of hippocampal neurons to study human neurogenesis and, more importantly, examine how human hippocampal cells, including granulated neurons and glia support, can be affected very early in Alzheimer’s disease and disorders where the hippocampus is injured.
“Using the patient’s iPSC, we can generate young brain cells and examine early pathogenic changes, and gain valuable information about the development and progression of brain disease,” said Laurent Roybon, director of the Stem Cell Laboratory for modeling CNS disease at Lund University and one of the researchers behind the study.
Understanding the patient’s own pathology
The researchers also used HS to examine cellular dysfunction in Alzheimer’s disease and more specifically, how cellular pathogenesis differed between individuals.
They generated HS from patients with extreme symptomatology – a typical Alzheimer patient carrying a mutation in the gene for the amyloid precursor protein, and an atypical individual carrying a rare mutation in the gene for presenilin 1 – and examined cell pathology.
Interestingly, we found that despite some important common characteristics, the HS of the two mutants differed in many other characteristics, which somewhat reflected the severity of their symptoms.. “
Yuriy Pomeshchik, lead author of the study, Lund University
Hippocampal spheroids can serve several purposes
The work developed in Dr. Roybon’s laboratory opens up new possibilities, as it serves several purposes:
“HS can be used to understand how hippocampal cells are generated and mature over time. They can also be used to examine whether neurogenesis is affected in HS generated by patients with hippocampal lesions compared to control individuals.
Analysis of HS can reveal which cellular dysfunctions occur at the start of the disease and whether they are identical or different between patients with familial or idiopathic forms. HS could be used to develop treatments adapted to subgroups of patients as well as to understand why certain treatments may or may not be beneficial to them.
Ultimately, HS could provide an opportunity to examine the effectiveness of putative treatment before it is administered, in addition to being used as a subgroup of people for a clinical trial and recruiting putative responders .
We believe that HS will be an important tool for developing therapies and offering patients the best possible treatment, “explains Laurent Roybon.
“We used HS to examine the effect of a gene called NeuroD1, which we have been studying in depth for years. Viral-mediated expression of NeuroD1 was sufficient to increase the level of synaptic genes, the levels of which are affected in Alzheimer’s disease.
Improving synaptic transmission will be essential to solving cognitive impairment in Alzheimer’s disease, “said Yuriy Pomeshchik.
“We will continue our efforts to generate spheroids from patients diagnosed with neurodegenerative diseases, and use them to obtain information on early cell dysfunction in order to identify disease-specific targets relevant for therapeutic intervention.” We are also going to push to bring NeuroD1 gene therapy to clinical trials “, concludes Laurent Roybon.
Using a similar methodology, the researchers also generated middle brain spheroids containing dopaminergic neurons to identify early metabolic dysfunctions in Parkinson’s cells (Chumarina et al, Acta Neuropathologica Communications, 2019).
Pomeshchik, Y., et al. (2020) Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cell Phenotypes and Developing Therapies. Stem cell reports. doi.org/10.1016/j.stemcr.2020.06.001.