Alpha-Secretase Modulation in Alzheimer's Disease

Alzheimer’s disease is characterised by the accumulation of neurotoxic amyloid-β peptides, generated through sequential β- and γ-secretase cleavage of the amyloid precursor protein (APP). In contrast, α-secretase cleavage of APP occurs within the amyloid-β domain, preventing peptide formation and releasing a neuroprotective fragment, sAPPα. The principal α-secretase in neurons is A Disintegrin And Metalloproteinase 10 (ADAM10), whose activity and expression are tightly regulated at transcriptional, translational and post-translational levels. Modulating α-secretase therefore offers a dual advantage: reducing amyloid load while supporting synaptic health through sAPPα-mediated signalling. Recent efforts have explored small-molecule enhancers, natural compounds and genetic regulators to upregulate ADAM10 or boost its maturation and trafficking. Advances in understanding the interplay between mitochondrial quality control, RNA-binding proteins and secretase expression have uncovered novel routes to promote non-amyloidogenic processing. Although challenges remain in achieving substrate selectivity and avoiding off-target effects, α-secretase modulation stands as a promising avenue for disease modification, with global implications for early intervention and improved clinical outcomes.

Research from Nature Portfolio

A seminal study repurposed a well-known pharmacological agent to enhance ADAM10 expression. Acute administration of this compound in a transgenic mouse model of Alzheimer’s disease induced peripheral and central upregulation of ADAM10, increased levels of sAPPα, and attenuated amyloid plaque burden, leading to measurable improvements in behavioural assays. Parallel analyses in treated patients demonstrated elevated ADAM10 expression in blood cells, suggesting feasibility of repurposing existing drugs to promote α-secretase activity in human populations.

Alpha-Secretase Modulation in Alzheimer's Disease publication trend

The graph below shows the total number of articles in alpha-secretase modulation in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Alpha-secretase: A protease that cleaves APP within the amyloid-β sequence, diverting it into a non-amyloidogenic pathway and releasing neuroprotective sAPPα.

ADAM10: A Disintegrin And Metalloproteinase 10; the principal physiological α-secretase in neurons responsible for non-amyloidogenic APP processing.

Amyloid precursor protein (APP): A transmembrane protein whose proteolytic fragments include amyloid-β peptides when cleaved by β- and γ-secretases, or sAPPα when cleaved by α-secretase.

Non-amyloidogenic pathway: The processing route of APP initiated by α-secretase cleavage, which precludes the formation of amyloid-β peptides.

5′ untranslated region (5′UTR): The mRNA segment upstream of the start codon that can regulate translation initiation through interaction with RNA-binding proteins.

Mitophagy: Selective autophagic degradation of mitochondria, which can influence the maturation and trafficking of membrane proteins such as ADAM10.

Small-molecule modulator: A low-molecular-weight compound designed to interact with specific proteins or pathways to upregulate α-secretase activity or expression.

References

1. SHMT2 Mediates Small‐Molecule‐Induced Alleviation of Alzheimer Pathology Via the 5′UTR‐dependent ADAM10 Translation Initiation. Advanced Science (2024).
2. Therapeutic potential of ADAM10 modulation in Alzheimer’s disease: a review of the current evidence. Cell Communication and Signaling (2023).
3. Alpha-lipoic acid alleviates cognitive deficits in transgenic APP23/PS45 mice through a mitophagy-mediated increase in ADAM10 α-secretase cleavage of APP. Alzheimer's Research & Therapy (2024).