amyloid precursor protein biosynthetic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of amyloid precursor protein (APP), the precursor of amyloid-beta, a glycoprotein associated with Alzheimer's disease. [GOC:go_curators]

The amyloid precursor protein (APP) biosynthetic process is a complex and tightly regulated pathway that involves the production, processing, and eventual degradation of APP, a transmembrane protein found in neurons and other cells. Here's a detailed description:

1. **Transcription and Translation:** The process begins with the transcription of the APP gene, located on chromosome 21, into messenger RNA (mRNA). The mRNA then travels to ribosomes in the endoplasmic reticulum (ER) where it is translated into the APP polypeptide chain.

2. **ER Translocation and Glycosylation:** The newly synthesized APP polypeptide chain enters the ER lumen, where it undergoes a series of modifications. These include:
* **N-linked glycosylation:** Sugars are added to specific asparagine residues within the APP molecule.
* **Folding and Chaperone Interactions:** The polypeptide chain folds into its correct three-dimensional structure with the help of chaperone proteins.

3. **Golgi Apparatus Processing:** After folding, APP translocates from the ER to the Golgi apparatus, where it undergoes further modifications:
* **Additional Glycosylation:** Further N-linked glycosylation occurs, and O-linked glycosylation can also take place.
* **Proteolytic Cleavage:** The APP molecule can be cleaved by different enzymes, including alpha-secretase and beta-secretase.
* **Alpha-secretase cleavage:** Occurs within the Abeta domain, preventing the formation of amyloid beta peptides. This results in the production of soluble APP alpha (sAPPalpha), which is thought to have neuroprotective effects.
* **Beta-secretase cleavage:** Occurs at the N-terminus of the Abeta domain, releasing soluble APP beta (sAPPbeta) and generating a C-terminal fragment (CTFbeta).

4. **Gamma-Secretase Cleavage and Abeta Formation:** CTFbeta can be further cleaved by gamma-secretase, a multi-protein complex, resulting in the production of amyloid beta (Abeta) peptides of different lengths, including the toxic Abeta40 and Abeta42.

5. **Abeta Aggregation and Deposition:** Abeta peptides can aggregate into oligomers and fibrils, which are thought to play a role in the development of Alzheimer's disease.

6. **Degradation:** APP and its fragments can be degraded by various pathways, including lysosomal degradation.

7. **Regulation and Control:** The APP biosynthetic process is tightly regulated by various factors, including:
* **Transcriptional control:** Expression of the APP gene can be influenced by factors such as neuronal activity and aging.
* **Post-translational modifications:** Modifications like phosphorylation and glycosylation can regulate APP trafficking and processing.
* **Protease activity:** The activity of alpha-, beta-, and gamma-secretases can be influenced by various factors, including cellular signaling pathways.

The amyloid precursor protein biosynthetic process is essential for normal neuronal function, but its dysregulation can contribute to the development of Alzheimer's disease. Understanding the intricate details of this process is crucial for developing therapies that can modulate APP processing and reduce the formation of toxic Abeta peptides.'
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Proteins (1)

Compounds (21)