positive regulation of amyloid-beta formation

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of amyloid-beta formation. [GOC:dph, GOC:TermGenie, PMID:17098871]

The positive regulation of amyloid-beta (Aβ) formation is a complex process involving multiple cellular mechanisms that promote the production and accumulation of Aβ peptides, which are key contributors to Alzheimer's disease (AD). This process encompasses various levels of regulation, including:

**1. Increased Aβ Precursor Protein (APP) Production:**
- Enhanced transcription and translation of APP genes lead to increased levels of the APP protein, the precursor molecule for Aβ.
- Transcription factors such as AP-1, CREB, and NF-κB are known to regulate APP expression, and their activation can contribute to increased APP production.

**2. Altered APP Processing:**
- The amyloidogenic processing pathway of APP involves sequential cleavages by two enzymes, β-secretase (BACE1) and γ-secretase.
- Enhanced activity of BACE1, the enzyme that initiates the amyloidogenic pathway, leads to increased production of Aβ.
- Dysregulation of γ-secretase, which cleaves the C-terminal fragment of APP, can also contribute to Aβ accumulation.

**3. Reduced Aβ Clearance:**
- Impaired clearance mechanisms for Aβ contribute to its accumulation in the brain.
- This includes reduced degradation by enzymes like neprilysin and insulin-degrading enzyme (IDE) as well as impaired transport across the blood-brain barrier.

**4. Chaperone Dysregulation:**
- Molecular chaperones, such as heat shock proteins (HSPs), play a role in maintaining protein homeostasis and preventing aggregation.
- Dysregulation of chaperone function can contribute to Aβ aggregation and deposition.

**5. Oxidative Stress and Inflammation:**
- Oxidative stress and inflammation are common features in AD and can contribute to Aβ production.
- Reactive oxygen species (ROS) can promote APP processing and Aβ aggregation.
- Inflammatory cytokines, such as TNF-α and IL-1β, can also modulate APP metabolism and increase Aβ production.

**6. Genetic Factors:**
- Certain genetic variations, such as mutations in the APP, PSEN1, and PSEN2 genes, are associated with increased risk of AD and accelerated Aβ production.

Overall, positive regulation of Aβ formation involves a combination of factors that promote increased production, altered processing, reduced clearance, and impaired cellular defense mechanisms against Aβ aggregation. These processes ultimately contribute to the formation and deposition of amyloid plaques in the brain, a hallmark of Alzheimer's disease.
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Proteins (8)

Compounds (487)