Amyloid Pathogenesis in Neurodegenerative Diseases

The accumulation and misfolding of amyloid-β (Aβ) peptides lie at the heart of a range of neurodegenerative disorders, most notably Alzheimer’s disease. Under normal conditions, Aβ is generated by sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretase. Imbalances in production, clearance or aggregation foster the transformation of monomeric Aβ into soluble oligomers and eventually insoluble fibrils that deposit as extracellular plaques. Soluble oligomeric species disrupt synaptic transmission and provoke neuronal hyperexcitability, while fibrillar deposits trigger local inflammation and glial activation. Microglia, the brain’s resident immune cells, respond to plaques via surface receptors such as TREM2, phagocytosing debris but also releasing pro-inflammatory mediators that may exacerbate neuronal injury. This interplay between protein misfolding, synaptotoxicity and neuroinflammation underpins cognitive decline. Recent advances in in vivo imaging, biomarker development and molecular engineering have refined our understanding of the spatial-temporal dynamics of Aβ aggregation, offering new avenues to intercept the cascade at its earliest, most reversible stages. Global efforts now target each node of the cascade—monomer generation, oligomer formation, fibril deposition and glial response—to yield disease-modifying therapies and predictive diagnostics with worldwide public-health relevance.

Research from Nature Portfolio

Recent studies have demonstrated that selective scavenging of monomeric Aβ can halt the formation of neurotoxic oligomers and reverse early synaptic dysfunction. Using a bespoke Aβ-binding anticalin protein in transgenic mouse models, investigators showed suppression of hippocampal hyperactivity and prevention of glutamate accumulation even before plaque deposition. Biochemical analyses confirmed that monomer depletion forestalled oligomer assembly, thereby preserving neuronal network stability at prodromal stages. The work highlights the therapeutic potential of monomer-targeted interventions to intercept the amyloid cascade at its inception, offering a strategy distinct from plaque-focused immunotherapies.

Amyloid Pathogenesis in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in amyloid pathogenesis in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β (Aβ): Peptide cleaved from amyloid precursor protein that aggregates into neurotoxic forms.

Oligomers: Soluble assemblies of Aβ that impair synaptic transmission and plasticity.

Fibrils: Insoluble, β-sheet-rich aggregates of Aβ forming extracellular plaques.

Anticalin protein: Engineered binding protein designed to scavenge specific peptide targets.

Microglia: Resident immune cells of the central nervous system involved in debris clearance and inflammation.

TREM2: Triggering receptor expressed on myeloid cells 2, a microglial surface receptor that mediates phagocytosis.

References

1. β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer’s Disease. Nature Communications (2024).
2. Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2. Advanced Science (2024).
3. APP processing in Alzheimer's disease. Molecular Brain (2011).
4. Alzheimer's disease: synaptic dysfunction and Aβ. Molecular Neurodegeneration (2009).