A primary pathological feature of Alzheimer’s disease (AD) is the accumulation of clusters (plaques) of amyloid beta (Aβ) protein peptides in the brain.
The formation of these plaques is the result of a continuous process by which individual Aβ proteins join together, latching onto each other, one at a time, like adding links to a chain. (1) In the early part of this process these small chains of Aβ are soluble and are toxic to the nerves within the brain. (2) (3)
The most toxic of the soluble chains is called a protofibril. (4) Protofibrils are believed to contribute to the brain injury that occurs with AD and are considered to be the most toxic form of Aβ, having a primary role in the cognitive decline associated with this progressive, debilitating condition. (5)
Protofibrils cause injury to neurons in the brain, which in turn, can negatively impact cognitive function via multiple mechanisms. This not only increases the development of insoluble Aβ plaques but also increases direct damage to brain cell membranes and the connections that transmit signals between nerve cells or nerve cells and other cells. It is believed the reduction of protofibrils may prevent the progression of AD by reducing damage to neurons in the brain and cognitive dysfunction. (6)
References
1. Alzheimer’s Association. (2022). Brain Tour Part 2 - Alzheimer’s Effect. Retrieved September 27, 2023, from https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour_part_2
2. Chen, Gf., Xu, Th., Yan, Y. et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol. 2017;38:1205. https://doi.org/10.1038/aps.2017.28
3. Habashi M., Vulta S., Tripathi K., et al. Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers. Biophysics and Computational Biology. 2022;10.1073. https://www.pnas.org/doi/epdf/10.1073/pnas.2210766119
4. Hampel, H., Hardy, J., Blennow, K. et al. The Amyloid-β Pathway in Alzheimer’s Disease. Mol Psychiatry. 2021;26:5481–5503. https://doi.org/10.1038/s41380-021-01249-0
5. Amin L, Harris DA. Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nat Commun. 2021;12:3451. doi:10.1038/s41467-021-23507-z
6. Ono K, Tsuji M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease. Int J Mol Sci. 2020;21(3):952. doi: 10.3390/ijms21030952. PMID: 32023927; PMCID: PMC7037706.