6th Edition of Neurology World Conference 2026

Abstract

The locus coeruleus (LC) is the brain’s principal source of norepinephrine (NE), a neuromodulator critically involved in attention, stress response, and memory formation. Degeneration of LC neurons and dysregulation of NE have been increasingly implicated in the pathophysiology of Alzheimer’s disease (AD), preceding and potentially contributing to amyloid pathology. Amyloid-β42 (Aβ42), a key pathogenic peptide in AD, accumulates in regions of early LC degeneration and has been identified within noradrenergic neurons. However, the mechanistic role of NE in modulating endogenous Aβ42 remains poorly understood. In this study, we investigated the relationship between central NE tone and Aβ42 concentration using three complementary mouse models. First, we employed a genetic norepinephrine-deficient model (Dbh-IRES-Cre x floxed-Th), which eliminates NE specifically in adrenergic neurons while preserving dopaminergic transmission. Second, to evaluate the reversibility of NE’s effects, we utilized L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic NE precursor capable of restoring NE levels in deficient mice. Third, we examined norepinephrine transporter knockout (NET KO) mice, which exhibit elevated synaptic NE due to impaired reuptake. We quantified Aβ42 levels in both the LC and frontal cortex using ELISA. Gene expression analyses were performed to assess whether changes in Aβ42 were linked to altered amyloid precursor protein (APP) processing or other upstream mechanisms. In NE-deficient mice, Aβ42 concentrations were significantly reduced in both brain regions despite no changes in APP expression or processing enzymes. This reduction was reversed upon NE restoration via L-DOPS, with treated mice exhibiting elevated Aβ42 levels compared to wild-type controls. Additionally, NET KO mice displayed the highest Aβ42 concentrations, suggesting a dose-dependent relationship between NE levels and Aβ42 accumulation. These findings establish that NE plays a regulatory role in maintaining endogenous Aβ42 concentrations in vivo, independent of amyloid precursor processing. The data support a model in which NE modulates Aβ42 levels through post-translational or clearance mechanisms, potentially via adrenergic receptor-mediated signaling or microglial modulation. Understanding NE’s direct impact on Aβ42 biology provides new insight into the early neurochemical changes that precede AD pathology. These results suggest that targeting the noradrenergic system, especially in the prodromal stages of AD or in individuals with LC vulnerability, could offer a promising therapeutic avenue. Our findings also highlight the importance of LC-NE integrity in regulating pathogenic peptides and support further investigation into noradrenergic modulation as an early intervention strategy in neurodegenerative disease.