APP - Beta-Amyloid Precursor Protein | Elisa - Clia - Antibody - Protein

Background:

Beta-amyloid precursor protein (APP) is a type I transmembrane protein that is primarily expressed in the brain. It is best known for its involvement in Alzheimer's disease (AD).APP is a large protein, consisting of a single polypeptide chain with several domains. These include an extracellular N-terminal domain, a transmembrane domain, and a short intracellular C-terminal domain. The exact physiological function of APP is not fully understood, but it is believed to play a role in neuronal development, synapse formation, and repair of neuronal injury. It is also involved in cell adhesion and intracellular signaling.APP undergoes sequential proteolytic processing by enzymes called secretases. The most well-known processing pathway involves cleavage by β-secretase (BACE1) followed by γ-secretase. This cleavage releases a fragment called beta-amyloid, which can aggregate to form amyloid plaques, a hallmark of Alzheimer's disease pathology.

Protein Structure:

• Primary Structure: APP is a large protein, comprising 695 to 770 amino acids depending on the isoform. The most studied isoform in the brain is APP695.
• Secondary Structure: The protein contains several domains, including a large extracellular domain, a single transmembrane helix, and a small intracellular C-terminal domain.
• Tertiary Structure: The extracellular domain includes regions critical for interactions with other proteins and cell-surface receptors. The transmembrane domain spans the lipid bilayer, anchoring the protein in the membrane.
• Quaternary Structure: APP can form dimers and oligomers, which are thought to influence its processing and function.

Classification and Subtypes:

APP belongs to the amyloid precursor protein family, which includes amyloid precursor-like proteins (APLP1 and APLP2). These proteins share structural similarities but have distinct physiological roles. There are several isoforms of APP resulting from alternative splicing of its mRNA, with APP695, APP751, and APP770 being the most common.

Function and Biological Significance:

APP has several functions beyond its role in AD:

• Neuronal Growth and Repair: APP is involved in neuronal development, synaptic formation, and repair processes.
• Cell Adhesion and Migration: It interacts with various extracellular matrix components, influencing cell adhesion and migration.
• Neuroprotection: APP has been shown to have neuroprotective properties, potentially protecting neurons from excitotoxicity and oxidative stress.
• Synaptic Function: It plays a role in synaptic plasticity and transmission, which are essential for learning and memory.

Processing Pathways:

APP can be processed via two major pathways:

• Non-Amyloidogenic Pathway: In this pathway, APP is cleaved by alpha-secretase within the Aβ region, preventing the formation of amyloidogenic peptides. This cleavage releases soluble APP-alpha (sAPPα), which has neuroprotective properties.
• Amyloidogenic Pathway: In this pathway, APP is first cleaved by beta-secretase (BACE1) to produce a soluble APP-beta (sAPPβ) and a membrane-bound C-terminal fragment. This fragment is then cleaved by gamma-secretase to release Aβ peptides. Aggregation of these peptides forms amyloid plaques.

Interactions:

APP interacts with numerous proteins, including:

• Secretases: Alpha-, beta-, and gamma-secretases, which cleave APP in different regions.
• Receptor Proteins: Such as low-density lipoprotein receptor-related protein 1 (LRP1) and integrins, influencing cell signaling and adhesion.
• Adaptor Proteins: Including Fe65 and JIP1, which are involved in intracellular signaling pathways.

Clinical Issues:

• Alzheimer's Disease: Mutations in the APP gene and altered APP processing are linked to early-onset familial Alzheimer's disease. Accumulation of Aβ peptides and formation of amyloid plaques are central to AD pathogenesis.
• Down Syndrome: Individuals with Down syndrome, who have an extra copy of chromosome 21, often exhibit early-onset AD due to overexpression of APP.
• Potential Therapeutic Target: APP and its processing enzymes are major targets in the development of AD therapeutics. Strategies include beta-secretase inhibitors, gamma-secretase modulators, and approaches to enhance non-amyloidogenic APP processing.

Summary:

Beta-Amyloid Precursor Protein (APP) is a multifunctional protein involved in neuronal development, cell adhesion, and neuroprotection. Its processing can lead to the formation of beta-amyloid peptides, which are central to the pathology of Alzheimer's disease. APP interacts with a variety of proteins, influencing its functions and processing pathways. Understanding APP's roles and its implications in diseases like AD is crucial for developing effective therapeutic interventions.