Abeta42 - Amyloid beta 42 | Elisa - Clia - Antibody - Protein

Background:

The Beta-amyloid precursor protein (APP) is a type I transmembrane protein primarily expressed in the brain. APP is a large protein consisting of a single polypeptide chain with several domains, including an extracellular N-terminal domain, a transmembrane domain, and a short intracellular C-terminal domain. While the exact physiological function of APP remains incompletely understood, it is believed to contribute to neuronal development, synapse formation, repair of neuronal injury, cell adhesion, and intracellular signaling. APP undergoes sequential proteolytic processing by enzymes known as secretases. The most recognized processing pathway involves cleavage by β-secretase (BACE1) followed by γ-secretase, releasing a fragment called beta-amyloid, which can aggregate to form amyloid plaques, a hallmark of Alzheimer's pathology. Beta-amyloid is formed through the sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein with an uncertain function. APP can be processed by α-secretase, β-secretase, and γ-secretase. Initially, beta-amyloid is generated through the successive action of β and γ-secretases. Both enzymes produce the C-terminal end of the peptide and subsequently integrate into the transmembrane region of APP to generate isoforms ranging from 36 to 43 amino acids. The most common isoforms are Aβ40 and Aβ42, where the shorter isoform is generated due to cleavage occurring in the endoplasmic reticulum, while the longer isoform is cleaved in the trans-Golgi area. Aβ40 is the most prevalent isoform. Aβ42 is more fibrillogenic and therefore associated with the development of certain diseases. Mutations in APP associated with early stages of Alzheimer's are linked to an increase in Aβ42 production, hence therapy targeting Alzheimer's aims to regulate the activity of β and γ-secretases to favor greater Aβ40 production.

Protein Structure:

• Primary Structure: Aβ42 is a 42 amino acid peptide with the sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA.
• Secondary and Tertiary Structures: In aqueous solutions, Aβ42 can exist in multiple conformations, including alpha-helical, random coil, and beta-sheet structures. The beta-sheet conformation is particularly significant as it promotes the formation of insoluble fibrils.
• Quaternary Structure: Aβ42 aggregates into various oligomeric forms, protofibrils, and fibrils. These aggregates are the primary components of amyloid plaques in AD.

Classification and Subtypes:

Aβ peptides are classified based on their length, with Aβ42 and Aβ40 being the most studied forms. Aβ42 has a higher tendency to form toxic aggregates compared to Aβ40, making it more relevant in the context of AD.

Function and Biological Significance:

• Normal Function: The physiological role of Aβ42 remains unclear, but it may be involved in synaptic function and neuroprotection under normal conditions. It might also play roles in metal ion homeostasis and cellular signaling.
• Pathological Role: Aβ42 is central to the formation of amyloid plaques, which are a hallmark of AD. These plaques disrupt neuronal function and trigger neuroinflammatory processes, contributing to neurodegeneration.

Interactions:

• Cellular Receptors: Aβ42 interacts with several cell surface receptors, including NMDA receptors, nicotinic acetylcholine receptors, and the receptor for advanced glycation end products (RAGE). These interactions can lead to synaptic dysfunction, calcium dysregulation, and oxidative stress.
• Metal Ions: Aβ42 binds to metal ions such as zinc, copper, and iron, which can promote aggregation and increase oxidative stress.
• Tau Protein: Aβ42 can influence the hyperphosphorylation of tau protein, another key pathological feature of AD. The interaction between Aβ42 and tau contributes to the formation of neurofibrillary tangles.

Clinical Issues:

• Alzheimer’s Disease: Aβ42 is more closely linked to the onset and progression of AD than Aβ40. Its aggregation into plaques is a defining pathological feature of the disease.
• Diagnosis and Biomarkers: Elevated levels of Aβ42 in the brain and reduced levels in cerebrospinal fluid (CSF) are used as biomarkers for AD diagnosis. Imaging techniques like PET scans with Aβ42-specific tracers are also employed.
• Therapeutics: Therapies targeting Aβ42 include monoclonal antibodies designed to clear Aβ plaques, gamma-secretase inhibitors, and beta-secretase inhibitors. Efforts are also being made to develop small molecules that can prevent Aβ42 aggregation or promote its clearance.

Summary:

Amyloid beta 42 (Aβ42) is a critical peptide in the context of Alzheimer's disease, known for its high propensity to form toxic aggregates and amyloid plaques. Understanding its structure, interactions, and role in AD pathology is essential for developing effective diagnostic and therapeutic strategies. Despite its association with neurotoxicity, the precise physiological functions of Aβ42 remain an area of active research.