Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of prodromal Alzheimer’s disease

Alzheimer’s disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation and sleep disruptions years before the onset of frank memory impairment. A hallmark prodromal feature is the accumulation of hyperphosphorylated “pretangle” tau (pTau) in the locus coeruleus (LC), the brain’s primary source of norepinephrine (NE), prior to any other region. While clinical studies link LC tau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the ‘LC-first’ phenomenon observed in humans using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation coincided with anxiety- and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked LC activity, accompanied by astrocytic reactivity with no apparent neuronal death. Transcriptomic analysis identified upregulation of the pacemaker potassium/sodium channel Hcn2 in the LC, which may contribute to neuronal hyperexcitability. To further define molecular mechanisms linking pTau to behavioral and cellular phenotypes, we developed a cell type-specific proteomics approach, which revealed synaptic and metabolic alterations in LC neurons associated with tau pathology. Interestingly, early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic phenotypes. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying targets to address neuropsychiatric manifestations.