The importance of brain cell communication

In Alzheimer’s disease, disrupted communication between neurons (brain cells) leads to cell death, brain shrinkage and the development of characteristic symptoms such as the loss of recent memories.

Understanding how and why these changes in neuron communication occur is crucial to develop early interventions to slow or stop disease progression, preventing life-changing symptoms and preserving patients’ cognitive function.

The limitations of animal experiments in Alzheimer’s disease research

Despite extensive use, animal experiments fall short in Alzheimer’s disease research. Most animals don’t live long enough to naturally develop AD, and those that do show important differences in their brains and symptoms compared to humans.

To try to overcome these obstacles, Alzheimer’s disease research commonly uses transgenic mice and rats (animals that have been genetically altered to develop Alzheimer’s disease-like symptoms), but these experiments still have major limitations. Transgenic mice and rats don’t  develop the characteristic features of human Alzheimer’s disease, such as the abnormal build-up of the proteins amyloid (which form “plaques” around the neurons), and tau (which forms “tangles” within the neurons). Most transgenic animals only develop amyloid plaques OR tau tangles and can therefore only replicate some symptoms and aspects of the disease, but not the full picture. Because of this, animal experiments can provide misleading results in pre-clinical drug testing, where drugs with promising animal results can be ineffective or even dangerous to humans. Nonetheless, these approaches are considered the ‘gold standard’ and thousands of animals are used in experiments each year, highlighting the need for alternative accurate and ethical research methods.

Advancing Alzheimer’s disease research with animal-free alternatives

Recent advancements in new approach methodologies (NAMs) offer promising alternatives to animal experiments in neurodegenerative research. Dr Thomas Piers, based at the University of Exeter, and his collaborator Dr Daniel Whitcomb at Bristol University are leveraging their expertise in these new technologies to study the early changes in neuron communication, which can’t be easily studied in animal experiments. Their work focusses on developing 3D ‘mini brain’ organoid models which include microglia (the immune cells of the brain). These ‘mini brains’ are grown from human stem cells (special cells that can be reprogrammed to become any type of cell in the body) and can be used to study neuron activity with state-of-the-art electrophysiological recording techniques.

The potential of ‘mini-brains’ for Alzheimer’s disease research

Dr Piers’ ‘mini brains’ provide an innovative, human-specific model to study how the microglia immune cells affect neurons’ ability to communicate. Microglia are thought to be important as mutated genes in these cells can lead to development of late onset Alzheimer’s disease (LOAD), which accounts for around 97% of Alzheimer’s disease cases. This is particularly important as LOAD can’t be studied using animals, providing a new, human-specific opportunity to understand this under-researched area.

Using ‘mini brains’ allows the study of the early stages of Alzheimer’s disease, helping to pinpoint opportunities for early intervention and the creation of drugs that could stop disease progression. This technology bridges the gap between the lab and the clinic, enabling the testing of new drugs to replace animal experiments and gain human-specific results.

Transitioning to animal-free science

Cells grown in 3D need a structure to help support them, known as a scaffold, however these scaffolds are often created using animal-derived materials. To reduce animal use in this type of research, Dr Piers will trial the replacement of animal-derived scaffolds such as Matrigel (a product derived from mouse tumours), with an animal-free alternative called GrowDex. This shift not only supports the ethical need to replace animal-derived products to carry out human research but will also enhance the relevance and translational ability of the research findings.

Sharing knowledge for wider impact

Dr Piers estimates that by using these human ‘mini brains’, around 200 rats could be saved each year, in his lab alone. If this model was used by other groups in similar research areas, this number saved could rise exponentially, all the while bringing us closer to developing new treatments for patients which are urgently needed.

Dr Piers is committed to sharing his animal-free methods with the broader research community, encouraging the adoption of these innovative approaches. By doing so, he aims to accelerate the transition to more humane and effective Alzheimer’s disease research, ultimately bringing us closer to breakthroughs in understanding this devastating disease.

To share his methods with other researchers, Dr Piers will attend the Alzheimer’s Research UK conference in 2025 and the Animal Welfare and Research 3Rs Symposium at the University of Bristol. Dr Piers also plans to attend several public engagement events throughout the project, including the Somerscience Festival in 2025, and he will also deliver a lay talk at a ‘Pint of Science’ event, an informal talk for the public by a scientist on their area of research. Here, he will explain animal use in neurodegenerative disease research, their limitations and what his group is doing to change this.