Alzheimer's disease is characterized by the slowly progressive destruction of nerve cells and nerve cell contacts. Typical protein deposits (amyloid plaques and tau fibrils) are found in the brains of Alzheimer's patients. Most of those affected are over 80 years old, only in rare cases does the disease begin before the age of 65. Hereditary forms of Alzheimer's disease are very rare.

Alzheimer's: Most of affected patients are older than 80, only in rare cases does the disease begin before the age of 65.
Graphic: Computer-generated.

There are high failure rates in clinical trials for Alzheimer's disease. Therefore, a better understanding of the pathophysiology and mechanisms of action of potential drugs is required. The research team has succeeded in replicating important biological aspects of ageing and senescence in a multicellular microphysiological system (MPS) or human-on-a-chip system.

The researchers cultivated nerve cells of the human cerebral cortex, which were obtained from induced pluripotent stem cells, and grew them on microelectrode arrays to measure non-invasively the amplification of synaptic transmission of a nerve cell in response to an increased formation of action potentials (long-term potentiation, LTP for short). Long-term potentiation is a quantifiable measure of learning and memory. It is directly affected by neurodegeneration in the CNS. The iPSC-derived neurons were experimentally exposed to pathogenic amyloid-β (Aβ), a peptide that plays a central role in the development of Alzheimer's disease. The aim was to mimic the pathophysiology of the disease. This allowed the research team to analyze senescence and potential therapeutic responses.

The model is an invaluable tool for real-time measurement of neuronal activity and ageing biomarkers, facilitating drug screening and the development of Alzheimer's therapies. In addition, complex disease mechanisms can be uncovered, such as the role of inflammatory factors in neuronal senescence.

Original publication:
Gallo LH, Akanda N, Autar K, et al. A functionally aged human iPSC-cortical neuron model recapitulates Alzheimer's disease, senescence, and the response to therapeutics. Alzheimer's Dement.2024; 1-21. https://doi.org/10.1002/alz.14044

Further information:
https://hesperosinc.com/new-study-in-alzheimers-and-dementia/

https://www.businesswire.com/news/home/20240730344393/en/New-Study-Describes-a-Functional-Aged-Human-Cell-Based-Platform-That-Examines-the-Contribution-of-Senescence-in-Alzheimer%E2%80%99s-Disease-Progression-and-Response-to-Therapeutics