amyloid precursor protein catabolic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the breakdown 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) catabolic process is a complex and tightly regulated pathway that involves the cleavage of APP by several enzymes, ultimately producing various peptides, including amyloid-beta (Aβ). APP is a type of transmembrane protein that plays a role in cell signaling and adhesion. Its catabolism is essential for maintaining normal brain function and preventing the accumulation of Aβ, which is associated with the development of Alzheimer's disease.

The APP catabolic process can be broadly divided into two major pathways:

1. **The Non-Amyloidogenic Pathway:** This pathway leads to the production of non-amyloidogenic fragments of APP. It is initiated by the α-secretase enzyme, which cleaves APP within the Aβ region, releasing a soluble APP fragment (sAPPα) and a membrane-bound C-terminal fragment (CTFα). CTFα is subsequently degraded by the γ-secretase complex, producing a small, non-amyloidogenic peptide.

2. **The Amyloidogenic Pathway:** This pathway leads to the production of Aβ. It begins with the β-secretase enzyme (BACE1), which cleaves APP within the Aβ region, releasing a soluble APP fragment (sAPPβ) and a membrane-bound CTFβ. CTFβ is then cleaved by the γ-secretase complex, resulting in the production of Aβ peptides of varying lengths.

The γ-secretase complex is a multi-protein complex that includes presenilin, nicastrin, Aph-1, and Pen-2. It is responsible for cleaving CTFα and CTFβ at multiple sites, generating various Aβ peptides. The most common form of Aβ is Aβ40, but Aβ42 is also produced and is considered more prone to aggregation.

The balance between the amyloidogenic and non-amyloidogenic pathways is crucial for regulating Aβ production. Factors that can influence this balance include:

- **APP expression levels:** Increased APP expression can lead to an increase in Aβ production.
- **Activity of the α-secretase, β-secretase, and γ-secretase enzymes:** The relative activity of these enzymes can determine the ratio of amyloidogenic to non-amyloidogenic APP processing.
- **Cellular conditions:** Various cellular conditions, such as oxidative stress and inflammation, can affect the activity of the enzymes involved in APP catabolism.

Dysregulation of the APP catabolic process, particularly an increase in the amyloidogenic pathway, can lead to the accumulation of Aβ in the brain. This accumulation can contribute to the formation of amyloid plaques, a hallmark of Alzheimer's disease. The plaques can disrupt neuronal function and lead to cognitive decline.

Therefore, understanding the complex interplay of factors that regulate APP catabolism is crucial for developing strategies to prevent or treat Alzheimer's disease.'
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Proteins (10)

Compounds (890)