EXPLORING NORADRENERGIC SIGNALING AND SLEEP PATTERNS IN PRODROMAL STAGES OF ALZHEIMER’S DISEASE MOUSE MODELS

The onset of Alzheimer’s disease (AD) is signaled by initially minute but ultimately disastrous physiological brain malfunctions. The noradrenaline (NA) -releasing and neuromelanin (NM) -accumulating Locus Coeruleus (LC) is among the areas that show malfunctions at the earliest stages of AD. As LC’s activity regulates sleep architecture, insights on how sleep disturbances relate to LC malfunctions could provide sensitive signatures of the earliest stages of AD.
We explore the functionality of the NA system in freely behaving APP^NL-F/MAPT knock-in mice (dKI), with or without virally induced NM accumulation. Biosensors for neuronal Ca²⁺ fluctuations (GCaMP8s) and free NA levels (GRAB_NE) are injected respectively in the LC and in the somatosensory thalamus or the hippocampus (CA1). In a subset of animals, the LC injection is paired with a human tyrosinase virus inducing NM accumulation. Within these mice, aged 12-18 months, we also record polysomnography (EEG/EMG), and local field potential (LFP) activity in the somatosensory cortex (S1) and CA1.
We investigate sleep parameters and their relationship to LC/NA activity. Our data indicates that dKI up to 17 months show preserved sleep and NA signaling. In contrast, within 4 weeks after NM accumulation induction, we observe a projection-specific vulnerability of LC activity patterns and disrupted sleep architecture that aggravates over time. We complement this data with histological assessment of NM and in vitro LC patch-clamp recordings.
Decoding the patterns of LC’s dysfunction during early stages of AD and their consequences on sleep could prove essential to early diagnosis and for interventions.