ETD

• alzheimer's disease
• brain aging
• locus coeruleus
• magnetic resonance imaging
• neuroinflammation
• neurovascular unit
• noradrenaline
• transmission electron microscopy
• unbiased stereology

The Locus Coeruleus (LC) is the brain’s primary source of noradrenaline (NA), a neurotransmitter critically involved in regulating neurovascular, glial, and immune homeostasis. Mounting evidence suggests that LC dysfunction plays a key role in Alzheimer’s disease (AD) pathogenesis, potentially contributing to the earliest stages of neurodegeneration. This thesis explored the hypothesis that LC impairment represents an upstream and active driver of AD-related pathology, influencing neuroinflammatory, vascular, and neuronal mechanisms.

This work adopted a translational approach, combining clinical neuroimaging studies in humans with experimental investigations in an animal model of chronic noradrenergic depletion. In the clinical phase, LC integrity was assessed through magnetic resonance imaging (MRI) in patients with AD and amnestic mild cognitive impairment (MCI). Our findings demonstrated that reduced LC-MRI signal correlates with plasma concentrations of soluble AXL—a biomarker of microglial activation—indicating a link between LC degeneration and systemic neuroinflammation. We further confirmed that LC degeneration is a progressive phenomenon in AD and observed that its interaction with cortical atrophy and cognitive decline may be influenced by sex and hormonal status.

In the experimental phase, a chronic LC lesion model was developed through repeated administration of the noradrenergic neurotoxin DSP-4 in ageing C57Bl/6J mice. Despite the absence of amyloid or tau pathology, LC-lesioned animals displayed multiple abnormalities reminiscent of AD-related mechanisms, including reduced hippocampal neuronal survival, thickening of the capillary basement membrane, impaired tight-junction maturation, and astroglial and microglial alterations—collectively indicating accelerated brain ageing and neurovascular dysfunction.

Together, these results provide converging clinical and experimental evidence supporting the “noradrenergic hypothesis” of AD, identifying LC impairment as a potential upstream contributor to disease pathogenesis. This work highlights the LC as both a promising biomarker of early AD and a potential therapeutic target. By elucidating how LC degeneration disrupts neurovascular and glial homeostasis, this thesis advances our understanding of AD as a multifactorial disorder in which neurodegeneration, inflammation, and vascular pathology converge upon a common noradrenergic vulnerability.