P3‐069: Elucidating the Relationship Between Hyperphosphorylated TAU and Locus Coeruleus Degeneration in Alzheimer’s Disease

Elucidating the mechanisms that initiate Alzheimer’s disease (AD) at its earliest stages is the key to effective therapeutics and diagnostics. The locus coeruleus (LC) is a brainstem nucleus that supplies noradrenaline to the forebrain and degenerates early in nearly all AD patients. The loss of the LC correlates with increasing severity of other hallmarks of AD such as beta-amyloid plaques, tau tangles and cognitive deficits. Recent studies suggest that a precursor form of tau pathology (hyperphosphorylated tau) can be found in the LC of young, cognitively normal individuals in the absence of other AD-like pathologies or neurodegeneration. However, the specific role of hyperphosphorylated tau and its contribution to LC degeneration are unclear. Here we investigated the relationship between hyperphosphorylated tau and degeneration of the LC both in vitro and in vivo. First, we crossed mice expressing green fluorescent protein driven by the tyrosine hydroxylase promoter with mice expressing a mutant human tau (P301S) that closely recapitulates AD tau pathology to culture primary LC neurons expressing aberrant tau and study their susceptibility to toxic challenges. We challenged the neurons with DSP-4, a noradrenergic toxin for 24 hours and measured neuronal death and neurite length. Next, we used DSP-4 to lesion the LC in P301S mice for 4, 6 and 10 months and investigated the impact of LC degeneration in P301S mice on neuropathology and cognitive impairments. In vitro, we found P301S tau has deleterious effects on LC neurite length and confers an extra susceptibility to cell death from exposure to DSP-4. In vivo,10 month old lesioned P301S mice had heightened postural phenotypes, irregularities in circadian rhythm, and impairments in social and spatial memory. These experiments highlight the impact of aberrant tau on LC cell survival and the subsequent role that LC degeneration may have on exacerbating tau pathology and cognitive impairments. These data lay the groundwork to understanding the initiation and progression of AD and could direct future diagnostics and therapeutics towards the LC and the noradrenergic system.