Norepinephrine-mediated regulation of endogenous Aβ₄₂ peptide levels: effects of noradrenergic depletion and restoration

Abstract

The locus coeruleus (LC), a cluster of noradrenergic neurons in the dorsal pons, is the brain’s main source of norepinephrine (NE), crucial for memory, cognition, and stress response. NE dysregulation has been linked to mood disorders, chronic stress, and neurodegenerative diseases like Alzheimer’s disease (AD). Amyloid-β₄₂ (Aβ₄₂) is a key protein in AD pathology, forms plaques that trigger neurodegeneration. Studies show elevated Aβ₄₂ levels are associated with anxiety symptoms, even in cognitively normal individuals. Previous research suggests a positive correlation between NE and Aβ₄₂, with Aβ₄₂ present in NE-producing LC neurons. NE may affect Aβ₄₂ levels through adrenergic receptors on neurons or microglia. However, the exact role of NE in modulating Aβ₄₂ remains unclear. Using the NE depletion models,  N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) lesions and dopamine β-hydroxylase (DBH) knockout (KO) mice, researchers found reduced Aβ₄₂ levels without changes in amyloid precursor protein processing. A newer model, dopamine β-hydroxylase internal ribosome entry site-Cre × floxed tyrosine hydroxylase (DBH-IRES-Cre × floxed-TH) preserved dopamine (DA) but eliminated NE in adrenergic neurons, further supporting NE’s specific influence on Aβ₄₂. Findings indicate that decreased Aβ₄₂ in NE-depleted mice stems not from altered DA but from NE loss. This highlights the NE-mediated regulation of endogenous Aβ₄₂ and NE’s role in AD-related pathology.

Keywords

amyloid / stress / norepinephrine / dopamine-β-hydroxylase / locus coeruleus

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Higher Education Press 2026

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