Adrenergic regulation of astroglial aerobic glycolysis and lipid metabolism: Towards a noradrenergic hypothesis of neurodegeneration

Ageing is a key factor in the development of cognitive decline and dementia, an increasing and challenging problem of the modern world. The most commonly diagnosed cognitive decline is related to Alzheimer's disease (AD), the pathophysiology of which is poorly understood. Several hypotheses have been proposed. The cholinergic hypothesis is the oldest, however, recently the noradrenergic system has been considered to have a role as well. The aim of this review is to provide evidence that supports the view that an impaired noradrenergic system is causally linked to AD. Although dementia is associated with neurodegeneration and loss of neurons, this likely develops due to a primary failure of homeostatic cells, astrocytes, abundant and heterogeneous neuroglial cells in the central nervous system (CNS). The many functions that astrocytes provide to maintain the viability of neural networks include the control of ionic balance, neurotransmitter turnover, synaptic connec-tivity and energy balance. This latter function is regulated by noradrenaline, released from the axon varicosities of neurons arising from the locus coeruleus (LC), the primary site of noradrenaline release in the CNS. The demise of the LC is linked to AD, whereby a hypometabolic CNS state is observed clinically. This is likely due to impaired release of noradrenaline in the AD brain during states of arousal, attention and awareness. These functions controlled by the LC are needed for learning and memory formation and require activation of the energy metabolism. In this review, we address first the process of neurodegeneration and cognitive decline, highlighting the function of astrocytes. Cholinergic and/or noradrenergic deficits lead to impaired astroglial function. Then, we focus on adrenergic control of astroglial aerobic glycolysis and lipid droplet metabolism, which play a pro-tective role but also promote neurodegeneration under some circumstances, supporting the noradrenergic hy-pothesis of cognitive decline. We conclude that targeting astroglial metabolism, glycolysis and/or mitochondrial processes may lead to important new developments in the future when searching for medicines to prevent or even halt cognitive decline.

Automated summary

Ageing is a major factor in the development of cognitive decline and dementia. The cholinergic hypothesis has long been considered the main cause of cognitive decline, but recent evidence suggests that an impaired noradrenergic system may also play a role in Alzheimer's disease. The review focuses on the role of astrocytes in neurodegeneration and cognitive decline, as well as the noradrenergic control of astroglial function.