Noradrenergic dysfunction in Alzheimer's disease

Abstract

The brain noradrenergic system supplies the neurotransmitter norepinephrine throughout the brain via widespread efferent projections, and plays a pivotal role in modulating cognitive activities in the cortex. Profound noradrenergic degeneration in Alzheimer's disease (AD) patients has been observed for decades, with recent research suggesting that the locus coeruleus (where noradrenergic neurons are mainly located) is a predominant site where AD-related pathology begins. Mounting evidence indicates that the loss of noradrenergic innervation greatly exacerbates AD pathogenesis and progression, although the precise roles of noradrenergic components in AD pathogenesis remain unclear. The aim of this review is to summarize current findings on noradrenergic dysfunction in AD, as well as to point out deficiencies in our knowledge where more research is needed.

Noradrenaline from Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM Sleep and Induces Its Loss-Associated Effects in Rats

“…Furthermore, it was also proposed that, if NAergic REM-OFF neurons do not cease activity, the NA level would rise in the brain and that elevated NA levels would be responsible for REMS loss-associated effects and symptoms. Indeed, our contention was supported by indirect, independent, and isolated experimental studies as well as by clinical observations (Mallick and Singh, 2011; Gannon et al, 2015); however, direct evidence particularly from in vivo studies was lacking. Therefore, in this study using tyrosine hydroxylase (TH)-siRNA and TH-shRNA in a separate group of normal rats, we downregulated TH in the LC neurons inhibiting NA synthesis in REM-OFF neurons.…”

Astrocytic transporters in Alzheimer's disease

“…While much of the research focuses on the cholinergic and glutamatergic pathways, recently scientists have proposed changes in a host of other neurotransmitters (174,175).…”

Noradrenergic Modulation of Cognition in Health and Disease

“…In vitro, NE increases IkB α [107], an inhibitor of proinflammatory transcription factor NF-kB. Inflammation is an important component in AD pathogenesis and promotes microglial activation [108], complement cascade, and inflammatory cytokine release [109] with nitric oxide activation. Animal studies have shown anti-inflammatory effects of pretreatment with a β -adrenergic receptor agonist [109] and α 2 receptor antagonist [110] on inflammation development in neurons after injection of β amyloid into LC-ablated animals.…”

“…Inflammation is an important component in AD pathogenesis and promotes microglial activation [108], complement cascade, and inflammatory cytokine release [109] with nitric oxide activation. Animal studies have shown anti-inflammatory effects of pretreatment with a β -adrenergic receptor agonist [109] and α 2 receptor antagonist [110] on inflammation development in neurons after injection of β amyloid into LC-ablated animals. It is important to note that some discrepancies exist between preclinical animal studies and clinical human studies: LC in animal AD models tends to be involved in late stages of pathology, compared to its degeneration in early disease progression in humans.…”