amyloid-beta metabolic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways involving amyloid-beta, a glycoprotein associated with Alzheimer's disease, and its precursor, amyloid precursor protein (APP). [GOC:ai]

Amyloid-beta (Aβ) metabolic process is a complex and multifaceted pathway involved in the production, processing, and clearance of Aβ peptides, small protein fragments that play a critical role in the pathogenesis of Alzheimer's disease.

**1. Production:** Aβ is generated from the amyloid precursor protein (APP), a transmembrane protein found in neurons and other cells. APP undergoes sequential proteolytic cleavage by two enzymes: β-secretase (BACE1) and γ-secretase.
* **β-secretase cleavage:** BACE1 cleaves APP within its extracellular domain, generating a soluble fragment called sAPPβ and a membrane-bound fragment called C99.
* **γ-secretase cleavage:** γ-secretase, a multiprotein complex, cleaves C99 at the transmembrane domain, releasing Aβ peptides of varying lengths, primarily Aβ40 and Aβ42.

**2. Aggregation:** Aβ peptides are highly hydrophobic and prone to aggregation, forming oligomers and fibrils.
* **Monomers:** Individual Aβ peptides initially exist as monomers.
* **Oligomers:** Monomers associate with each other, forming small, soluble aggregates called oligomers. These oligomers are highly toxic and believed to be the primary mediators of neuronal damage in Alzheimer's disease.
* **Fibrils:** Oligomers further aggregate into larger, insoluble fibrils, which are the hallmark of amyloid plaques found in the brains of Alzheimer's patients.

**3. Clearance:**
* **Degradation:** Aβ peptides can be degraded by various proteases, including neprilysin, insulin-degrading enzyme (IDE), and plasmin.
* **Efflux:** Aβ can be transported out of the brain through the blood-brain barrier by transporters like P-glycoprotein.
* **Glial uptake:** Microglia, the brain's resident immune cells, can phagocytose and degrade Aβ.

**4. Dysregulation in Alzheimer's Disease:**
* **Increased production:** Elevated levels of BACE1 or mutations in APP can lead to increased Aβ production.
* **Reduced clearance:** Deficiencies in Aβ degradation or efflux mechanisms can contribute to Aβ accumulation.
* **Abnormal aggregation:** Mutations in Aβ or other proteins can promote aberrant aggregation, leading to the formation of toxic oligomers and fibrils.

**The delicate balance between Aβ production, aggregation, and clearance is crucial for maintaining brain health. Dysregulation in this pathway, resulting in Aβ accumulation, is a key driver of Alzheimer's disease pathology.**'
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Proteins (6)

Compounds (262)