Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer’s disease

Abstract

Accumulation of hyperphosphorylated tau in the locus coeruleus (LC) is a ubiquitous feature of prodromal Alzheimers disease (AD), and LC neurons degenerate as AD progresses. Tau-mediated LC dysfunction may contribute to early neuropsychiatric symptoms, while loss of LC integrity is associated with conversion to cognitive impairment. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons have not been described. The purpose of this study was to characterize changes in firing properties of LC neurons when they are the only cells containing hyperphosphorylated tau, as well as later in disease when β-amyloid (Aβ) and tau pathology is abundant in the forebrain. Single unit LC activity was recorded from anesthetized wild-type (WT) and TgF344-AD rats, which carry the APP/PS1 transgene. Similar to human AD, these rats develop hyperphosphorylated tau in the LC (at 6 months) prior to Aβ or tau pathology in forebrain regions (at 12-15 months). At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates, but showed elevated spontaneous bursting properties, particularly in younger animals. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and aged transgenic rats showing hypoactivity relative to WT. Tau-induced alterations in LC firing rates may contribute to the pathophysiology of AD, with early hyperactivity associated with prodromal symptoms, followed by hypoactivity contributing to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.

The emotion paradox in the aging body and brain

“…Thus, findings that 1) older adults with higher entorhinal tau pathology showed lower LC responses to novelty and 2) patients with Alzheimer's disease have higher cerebrospinal fluid levels of noradrenaline than do cognitively normal controls, 111 are consistent with the possibility that Alzheimer's disease‐related pathology triggers noradrenergic hyperactivity. In addition, older rats with hyperphosphorylated tau infused into the LC show hyperactive tonic LC firing months later, when older 112 …”

“…In addition, older rats with hyperphosphorylated tau infused into the LC show hyperactive tonic LC firing months later, when older. 112 F I G U R E 3 Tonic LC activity levels (A) and intensity of phasic LC (B) responses to loud noise during active wake, quiet wake, and non-rapid eye movement (NREM) sleep. From Hayat et al 108 Although whether tonic LC activity increases with age and Alzheimer's disease is still debated 107 and needs better data to be resolved, based on available findings, the autonomic compensation model posits that hyperphosphorylated tau in the LC increases tonic noradrenergic activity within the brain and stimulates pregenual PFC regulatory processes to decrease tonic noradrenergic activity in the brain and periphery.…”