Noradrenergic depletion potentiates β‐amyloid induced cortical inflammation: implications for Alzheimer's disease

Abstract

Degeneration of locus ceruleus (LC) neurons and reduced levels of noradrenaline (NA) in LC projection areas is a well known feature of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Since inflammatory mediators contribute to AD pathogenesis, and since NA can suppress inflammatory gene expression, we tested if LC loss influenced brain inflammatory gene expression elicited by amyloid β (Aβ). Adult rats were injected with the selective neurotoxin DSP4 to induce LC death, and subsequently injected in cortex with Aβ (aggregated 1–42 peptide). DSP4‐treatment potentiated the Aβ‐dependent induction of inflammatory nitric oxide synthase (iNOS), IL‐1β and IL6 expression compared to control animals. In contrast, the induction of cyclooxygenase‐2 expression was not modified by DSP4‐treatment. In control animals, injection of Aβ induced iNOS primarily in microglial cells, while in DSP4‐treated animals iNOS was localized to neurons, as is observed in AD brains. Injection of Aβ increased IL‐1β expression initially in microglia, and at later times in astrocytes, and expression levels were greater in DSP4 treated animals than controls. The potentiating effects of DSP4‐treatment on iNOS and IL‐1β expression were attenuated by coinjection with NA or the β‐adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NA depletion augment inflammatory responses to Aβ, and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.