PROJECT SUMMARY Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting 55 million worldwide, and is typified by extracellular deposits of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Numerous clinical trials designed to alleviate cognitive symptoms by targeting Aβ pathology have failed. However, few studies have comprehensively examined the earlier, prodromal stages, which are characterized by anxiety, agitation, depression, and sleep-wake disturbances that significantly disrupt quality of life and ability to remain independent. The noradrenergic nucleus locus coeruleus (LC) modulates these physiological processes and is the first region to accumulate hyperphosphorylated ‘pretangle’ tau decades before cognitive deficits and Aβ plaques appear. It is therefore important to establish whether a causal relationship between LC tau pathology and prodromal symptoms exists because it can lead to development of therapeutic interventions that relieve these devastating non-cognitive symptoms and possibly halt disease progression. While catastrophic LC cell body degeneration occurs in late AD, the earlier prodromal phases are characterized by aberrant tau accumulation and reductions in LC innervations to projection regions. Moreover, there are suggestions that surviving LC neurons show compensatory increases in firing accompanied by elevations in forebrain adrenergic receptors, thus promoting noradrenergic hyperactivity that could underlie the prodromal symptoms. Since most animal models fail to recapitulate the pathological prodromal feature of hyperphosphorylated tau in the LC, I will develop a biologically valid mouse model where aberrant forms of tau are exclusively expressed in the LC using viral vector-mediated strategies. In Aim 1, I will determine if LC tau burden disrupts LC-sensitive behaviors relevant to prodromal symptoms and exacerbates neuropathology. In Aim 2, I will interrogate the genetic mechanisms that underlie tau-mediated LC dysregulation and degeneration by using Translating Ribosome Affinity Purification (TRAP) to selectively isolate the LC transcriptome and RNAscope in situ hybridization to assess downstream effects on adrenergic receptor gene expression in LC-projecting regions. I hypothesize that aberrant tau in the LC will cause behavioral abnormalities that are commonly associated with the prodromal phase of AD and disrupt normal noradrenergic transmission. Successful completion of these aims will reveal putative molecular mechanistic factors that underlie prodromal symptoms commonly experienced by AD patients and can yield disease-modifying targets for therapeutic interventions.