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Amyloid beta, structure, biology and structure-based therapeutic development

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Amyloid Beta (Aβ): Structure, Biology, and Therapeutic Development

Overview

Amyloid beta (Aβ) is a peptide derived from the amyloid precursor protein (APP) through proteolytic cleavage by β-secretase and γ-secretase. It is a crucial factor in the pathology of Alzheimer’s disease (AD) and is considered a toxic waste product in the brain.

Forms of Aβ

  • Soluble Aβ: Exists freely in the extracellular space.
  • Aβ Oligomers: Small aggregates that are highly toxic to neurons.
  • Aβ in Amyloid Plaques: Insoluble deposits found primarily in the neocortex and hippocampus of AD patients.

Toxicity and Pathology

  • Neurotoxicity: Aβ aggregates into fibrillar structures, forming plaques that are neurotoxic. These plaques are characteristic of Alzheimer’s disease.
  • Mitochondrial Dysfunction: Aβ oligomers induce oxidative stress and mitochondrial dysfunction, leading to neuronal damage.
  • Receptor Binding: Aβ binds to various receptors, including lipids, proteoglycans, and proteins, generating neurotoxic signals.
  • Inflammatory Responses: Aβ aggregation triggers inflammatory responses, damaging synapses and neurites.
  • Synaptic Damage: Aβ reduces synapse numbers, particularly affecting neurons that produce serotonin, norepinephrine, glutamate, or acetylcholine.

Role in Alzheimer’s Disease

  • Amyloid Cascade Hypothesis: Proposes that Aβ aggregation into plaques leads to neurotoxicity and dementia.
  • Neuronal Activity: Increased neuronal activity enhances α-secretase cleavage of APP, producing sAPPα and reducing Aβ production.
  • Vascular Implications: Aβ deposition in cerebral blood vessels, known as cerebral amyloid angiopathy (CAA), compromises vessel integrity, leading to hemorrhages.

Aβ Degradation and Clearance

  • Proteolytic Degradation: A critical process in regulating cerebral Aβ levels, involving enzymes like neprilysin (NEP) and endothelin-converting enzymes (ECEs).
  • Glymphatic System: Facilitates Aβ clearance, with 65% of exogenously delivered Aβ cleared during sleep.
  • Active Transport and Aggregation: Aβ is actively transported out of the brain or deposited into insoluble aggregates.

Therapeutic Implications

  • Antimicrobial Properties: Aβ functions similarly to antimicrobial peptides, inhibiting pathogen growth and suggesting a dual role in innate immunity and AD pathology.
  • Future Strategies: Understanding Aβ’s dual role may inform the development of novel AD treatments targeting both its neurotoxic and antimicrobial functions.

Additional Information

  • Receptor Interactions: Aβ binds to the p75NTR receptor, inducing apoptosis in neuroblastoma cells.
  • Chronic Immune Response: Sustained Aβ levels may trigger chronic innate immune responses, exacerbating AD pathology.

This structured overview highlights the complexity of Aβ’s role in Alzheimer’s disease and its potential as a target for therapeutic intervention.

see also

Tags: neuroscience science
Superlink: 050 🧠Neuroscience
051 ☣Neurobiology
Memory in Sleep

Source

Chen, G., Xu, T., Yan, Y., Zhou, Y., Jiang, Y., Melcher, K., & Xu, H. E. (2017). Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacologica Sinica, 38(9), 1205-1235. https://doi.org/10.1038/aps.2017.28

Created: 30-01-24 18:06