Noradrenaline in the aging brain: Promoting cognitive reserve or accelerating Alzheimer's disease?

Abstract

Many believe that engaging in novel and mentally challenging activities promotes brain health and prevents Alzheimer's disease in later life. However, mental stimulation may also have risks as well as benefits. As neurons release neurotransmitters, they often also release amyloid peptides and tau proteins into the extracellular space. These by-products of neural activity can aggregate into the tau tangle and amyloid plaque signatures of Alzheimer's disease. Over time, more active brain regions accumulate more pathology. Thus, increasing brain activity can have a cost. But the neuromodulator noradrenaline, released during novel and mentally stimulating events, may have some protective effects-as well as some negative effects. Via its inhibitory and excitatory effects on neurons and microglia, noradrenaline sometimes prevents and sometimes accelerates the production and accumulation of amyloid-β and tau in various brain regions. Both α2A- and β-adrenergic receptors influence amyloid-β production and tau hyperphosphorylation. Adrenergic activity also influences clearance of amyloid-β and tau. Furthermore, some findings suggest that Alzheimer's disease increases noradrenergic activity, at least in its early phases. Because older brains clear the by-products of synaptic activity less effectively, increased synaptic activity in the older brain risks accelerating the accumulation of Alzheimer's pathology more than it does in the younger brain.

Keywords: Aging; Alzheimer’s disease; Glutamatergic activity; Locus coeruleus.

Figure 1

Aspects of noradrenergic hot spots that may contribute to modulating Aβ and tau release and their impact: 1) Increased vesicle trafficking due to synaptic activity is associated with increased release of Aβ and tau; 2) Increased glutamate release is associated with increased tau release; and 3) β-adrenergic microglial activation modulates toxic effects of Aβ. Figure created with BioRender.com.