β-Secretase Mechanisms in Alzheimer's Disease Pathology

β-Secretase refers to the enzymatic activity that initiates cleavage of amyloid precursor protein (APP) at the β-site, generating the N-terminus of amyloid-β (Aβ) peptides. The principal brain β-secretase, BACE1, is an aspartyl protease that operates predominantly within endosomal compartments. Following β-secretase action, the γ-secretase complex further processes the remaining APP fragment to release Aβ species, notably Aβ42, which aggregate into oligomers, fibrils and extracellular plaques characteristic of Alzheimer’s disease. Elevated BACE1 expression and activity in affected brains drive pathological Aβ accumulation, synaptic dysfunction and neurodegenerative cascades. Beyond APP, BACE1 cleaves multiple neuronal substrates—such as cell adhesion molecules and cytokine receptors—thereby influencing synaptic plasticity, neuroinflammation and neuronal survival. Its homologue BACE2, while sharing structural similarity, exhibits distinct substrate specificity and physiological roles, particularly in vascular and peripheral tissues. Dysregulation of β-secretase activity therefore represents a central molecular mechanism in Alzheimer’s pathogenesis and remains a focal point for therapeutic intervention aimed at reducing Aβ burden without compromising essential proteolytic functions.

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β-Secretase Mechanisms in Alzheimer's Disease Pathology publication trend

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Technical terms

β-Secretase (BACE1): Lysosomal aspartyl protease that cleaves APP at the β-site to initiate Aβ production.

BACE2: Homologous protease to BACE1 with distinct substrate specificity and roles in peripheral and vascular tissues.

Amyloid precursor protein (APP): Type I transmembrane protein that, upon β- and γ-secretase cleavage, yields amyloid-β peptides.

Amyloid-β (Aβ): Peptides of variable length derived from APP that aggregate into neurotoxic oligomers and extracellular plaques.

Ectodomain shedding: Proteolytic release of a membrane protein’s extracellular region, modulating receptor signalling and clearance.

Endosome: Intracellular compartment where BACE1 predominantly cleaves APP and other substrates under acidic conditions.

References

1. The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Molecular Neurodegeneration (2023).
2. The Alzheimer’s disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling. Journal of Clinical Investigation (2024).