Abeta40 - Amyloid beta 40 | 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: Aβ40 is a 40 amino acid peptide derived from the transmembrane APP. The amino acid sequence of Aβ40 is as follows: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA.
• Secondary and Tertiary Structures: In solution, Aβ40 can adopt alpha-helical, random coil, or beta-sheet conformations. The beta-sheet conformation is particularly significant as it leads to the formation of amyloid fibrils and plaques.
• Quaternary Structure: Aβ40 can aggregate into soluble oligomers, protofibrils, and insoluble fibrils, which are major components of the amyloid plaques found in the brains of AD patients.

Classification and Subtypes:

Aβ peptides, including Aβ40, are classified based on their length, which is determined by the site of gamma-secretase cleavage. The two most common forms are Aβ40 and Aβ42, with Aβ40 being less prone to aggregation compared to Aβ42.

Function and Biological Significance:

• Normal Function: Under physiological conditions, Aβ40 and other Aβ peptides might play roles in synaptic function, neuroprotection, and metal ion homeostasis. However, these roles are not fully understood.
• Pathological Role: Aβ40 contributes to the formation of amyloid plaques in AD. Although less prone to aggregation than Aβ42, Aβ40 can co-aggregate with Aβ42, stabilizing plaques and contributing to neurotoxicity.

Interactions:

• Cellular Receptors: Aβ40 interacts with various cell surface receptors, including the NMDA receptor, RAGE (receptor for advanced glycation end products), and certain integrins. These interactions can lead to synaptic dysfunction, oxidative stress, and inflammation.
• Metal Ions: Aβ40 binds to metal ions such as zinc, copper, and iron, which can promote its aggregation and contribute to oxidative stress.
• Other Aβ Isoforms: Aβ40 interacts with Aβ42 and other isoforms, influencing the aggregation dynamics and toxicity of amyloid plaques.

Clinical Issues:

• Alzheimer's Disease: The accumulation of Aβ40, along with Aβ42, is a hallmark of AD. While Aβ42 is more fibrillogenic, Aβ40 contributes significantly to the overall amyloid burden and plaque formation.
• Cerebral Amyloid Angiopathy (CAA): Aβ40 is particularly associated with CAA, a condition characterized by the deposition of amyloid in the walls of cerebral blood vessels, leading to increased risk of hemorrhage and stroke.
• Diagnostics and Therapeutics: Aβ40 levels in cerebrospinal fluid (CSF) and blood are used as biomarkers for AD diagnosis and progression. Therapeutic strategies targeting Aβ40 include immunotherapy, gamma-secretase inhibitors, and aggregation inhibitors.

Summary:

Amyloid beta 40 (Aβ40) is a significant peptide in the context of Alzheimer's disease and cerebral amyloid angiopathy. Despite being less prone to aggregation than Aβ42, Aβ40 contributes to the formation and stability of amyloid plaques, playing a critical role in AD pathology. Understanding the interactions and aggregation properties of Aβ40 is crucial for developing therapeutic strategies aimed at mitigating its neurotoxic effects.