Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic
terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer’s
disease (AD) and Down syndrome (DS) are characterized by similar pathology including
significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals
has been linked to alterations in brain regions vital for cognition, mood, and executive function.
While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are
not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive
decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing.
Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs,
and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic
system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.
Keywords: Adrenergic system, Alzheimer’s disease, β-Adrenergic, Monoaminergic systems, Down syndrome, Dementia,
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