Targeting norepinephrine in mild cognitive impairment and Alzheimer's disease

Abstract

The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.

Figure 1

Enhancing norepinephrine may be a promising strategy to treat Alzheimer's disease. (a) Plaque deposition in the hippocampus (HP) and cortex (CTX) of 1-year-old APP/PS1 mice (NET WT,APP/PS1) and norepinephrine transporter knockout APP/PS1 mice (NET KO,APP/PS1) as detected by immunohistochemistry using antiserum 2964 against fibrillar Aβ42. (b) Abundance of full-length amyloid precursor protein (APP), the APP C-terminal fragment (CTF), and Aβ in male and female NET WT,APP/PS1 and NET KO,APP/ PS1 mice at 6 months of age as detected by western blot using mAb 6E10 against amino acid residues 1 to 16 of Aβ. Tubulin was used as a loading control. Aβ, amyloid-beta; NET WT, norepinephrine transporter wildtype; PS1, presenilin-1.