Background
The human brain consists of around 100 billion nerve cells, known as neurons, each of which establishes connections with numerous others, forming intricate communication networks. These groups of nerve cells undertake specific functions; some are engaged in cognitive processes such as thinking, learning, and memory, while others contribute to sensory perceptions like vision, hearing, and smell.
Functioning akin to miniature factories, brain cells perform a multitude of tasks. They acquire necessary resources, produce energy, manufacture essential components, and eliminate waste materials. Additionally, these cells handle information processing and storage, all the while engaging in intercellular communication. Sustaining these intricate operations necessitates meticulous coordination, along with substantial supplies of fuel and oxygen.
Alzheimer's disease, discovered by Alois Alzheimer in 1906, is a disease affecting the brain characterised by cognitive decline, memory loss, and behavioural changes. The disease results from abnormal protein aggregation, primarily amyloid-beta plaques and tau tangles in the brain, damaging and killing the brain cells. In this essay, we will look closer at the role of amyloid-beta (Aβ) in Alzheimer’s disease.
Formation of Aβ plaques
The Aβ peptide is cleaved from a much larger protein called the amyloid precursor protein (APP) using two alternative pathways resulting in different outcomes. In patients of Alzheimer’s disease, the cleaved Aβ clumps together forming sticky plagues that accumulate between neurons disrupting communication and promoting inflammation. This accumulation triggers a chain reaction, inducing oxidative stress and activating immune responses that progressively damage brain cells. The toxic buildup of Aβ disrupts the delicate equilibrium of brain function, leading to cognitive decline, memory loss, and other debilitating symptoms characteristic of Alzheimer's.
Three-dimensional (3D) structure of Aβ
Understanding the 3D structure of the Aβ is crucial for uncovering the pathogenesis of the disease and for designing targeted therapeutic interventions. X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and cryo-electron microscopy (cryo-EM) have provided insights into Aβ's structure. It is recognized that Aβ peptides can adopt various conformations, ranging from random coils to β-sheet-rich aggregates (Figure 1). The β-sheet structures play a pivotal role in Aβ aggregation, leading to the formation of toxic oligomers and fibrils. Recent advances in cryo-EM have allowed researchers to visualise the intricate details of Aβ fibrils, which has enhanced our comprehension of their structure and organisation.
Therapeutic approaches for treating Alzheimer’s disease
In the pursuit of therapeutic strategies for Alzheimer's disease, targeting Aβ has emerged as a primary avenue. Several approaches have been explored, including inhibition of Aβ production, clearance of existing Aβ aggregates, and modulation of Aβ aggregation propensity. Clinical trials have investigated compounds aimed at inhibiting β-secretase or γ-secretase to reduce Aβ production, but these approaches have faced challenges due to non-specific effects on other cellular processes. Another strategy involves the use of monoclonal antibodies that specifically target Aβ aggregates and promote their clearance by the immune system. One such example is the monoclonal antibody solanezumab (Figure 2), which has shown promising results in reducing Aβ plaque accumulation in clinical trials.
Sri Appasamy
About the artwork
Amelia Mittal, a Year 12 student at The Leys School in Cambridge, created a textile artwork featuring a ball of wool to symbolise the abnormal buildup of proteins that leads to Alzheimer’s disease. The intricate artwork was crafted through a combination of felt sculpting, etching, and printmaking on feathers.
View the artwork in the .
Relevant structures
Structure of Aβ peptide (PDB 1IYT)
Structure of Aβ fibril (PDB 5OQV)
Short fragment of Aβ peptide complexed with the antibody solanezumab (PDB 4XXD)
Relevant references
