Amyloid beta

Introduction

Amyloid beta (Aβ) is a peptide of 36–43 amino acids that is crucially involved in the pathogenesis of Alzheimer's disease (AD). It is derived from the amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. The aggregation of amyloid beta into plaques is a hallmark of AD, contributing to neurodegeneration and cognitive decline.

Structure and Formation

Amyloid beta is produced through the proteolytic cleavage of APP, a transmembrane protein. The cleavage process involves two key enzymes: β-secretase (BACE1) and γ-secretase. Initially, BACE1 cleaves APP to produce a soluble fragment and a membrane-bound fragment known as C99. Subsequently, γ-secretase cleaves C99 within the membrane, releasing amyloid beta peptides of varying lengths, predominantly Aβ40 and Aβ42.

3D structure of amyloid beta peptide.

3D structure of amyloid beta peptide.

The Aβ42 variant is more prone to aggregation than Aβ40 and is considered more pathogenic. The propensity of amyloid beta to form oligomers, protofibrils, and fibrils is a key factor in its neurotoxicity.

Aggregation and Plaque Formation

Amyloid beta peptides can aggregate into soluble oligomers, which are believed to be the most toxic form. These oligomers can further assemble into protofibrils and mature fibrils, eventually forming the amyloid plaques observed in the brains of Alzheimer's patients. The aggregation process is influenced by various factors, including peptide concentration, pH, and the presence of metal ions such as zinc and copper.

The amyloid plaques are extracellular deposits primarily composed of amyloid beta fibrils. These plaques disrupt cell-to-cell communication and activate immune responses, leading to inflammation and neuronal damage.

Role in Alzheimer's Disease

The amyloid cascade hypothesis posits that the accumulation of amyloid beta is the initial pathological event in Alzheimer's disease, leading to tau pathology, neuroinflammation, and neurodegeneration. Amyloid beta oligomers are particularly toxic, impairing synaptic function and plasticity, which are critical for learning and memory.

The presence of amyloid plaques is one of the diagnostic criteria for Alzheimer's disease, along with neurofibrillary tangles composed of hyperphosphorylated tau protein. However, the exact mechanisms by which amyloid beta contributes to neurodegeneration remain an area of active research.

Mechanisms of Toxicity

Amyloid beta exerts its toxic effects through multiple mechanisms:

• **Synaptic Dysfunction**: Amyloid beta oligomers interfere with synaptic transmission and plasticity, leading to cognitive deficits. They disrupt long-term potentiation (LTP), a process essential for memory formation.

• **Oxidative Stress**: Amyloid beta can generate reactive oxygen species (ROS), leading to oxidative damage to proteins, lipids, and DNA. This oxidative stress contributes to neuronal injury and death.

• **Membrane Disruption**: Amyloid beta can insert into cell membranes, forming ion-permeable channels that disrupt cellular homeostasis. This can lead to calcium dysregulation and cell death.

• **Inflammation**: Amyloid beta activates microglia and astrocytes, the brain's immune cells, triggering an inflammatory response. Chronic inflammation exacerbates neuronal damage and disease progression.

Therapeutic Approaches

Several therapeutic strategies targeting amyloid beta are being explored:

• **β-Secretase Inhibitors**: These drugs aim to reduce the production of amyloid beta by inhibiting the activity of BACE1. Examples include verubecestat and lanabecestat.

• **γ-Secretase Modulators**: These compounds selectively modulate γ-secretase activity to reduce the production of the more pathogenic Aβ42 variant. Semagacestat and avagacestat are examples of γ-secretase inhibitors.

• **Immunotherapy**: Both active and passive immunotherapies are being developed to promote the clearance of amyloid beta from the brain. Aducanumab, a monoclonal antibody targeting amyloid beta, has been approved for the treatment of Alzheimer's disease.

• **Aggregation Inhibitors**: These agents aim to prevent the aggregation of amyloid beta into toxic oligomers and fibrils. Examples include tramiprosate and scyllo-inositol.

Research and Controversies

The amyloid hypothesis has been the dominant framework for Alzheimer's research for decades. However, it has faced criticism due to the failure of many amyloid-targeting therapies in clinical trials. Some researchers argue that amyloid beta is a downstream effect rather than the primary cause of Alzheimer's disease.

Recent studies suggest that amyloid beta may have physiological functions, such as antimicrobial activity and regulation of synaptic activity. This has led to a more nuanced understanding of its role in health and disease.

Future Directions

Ongoing research aims to elucidate the precise mechanisms by which amyloid beta contributes to Alzheimer's disease and to develop more effective therapies. Advances in imaging techniques, such as positron emission tomography (PET), allow for the visualization of amyloid plaques in living patients, aiding in diagnosis and monitoring of disease progression.

Combination therapies targeting multiple aspects of the disease, including amyloid beta, tau, and neuroinflammation, are being explored. Personalized medicine approaches, taking into account genetic and biomarker profiles, may also improve treatment outcomes.

See Also

• Alzheimer's Disease
• Amyloid Precursor Protein
• Neurofibrillary Tangles
• Oxidative Stress
• Microglia