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.

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

“…Activation of b2-ARs may also have a key role in the ability of environmental enrichment to reduce the effects of Ab peptides on synaptic plasticity (Li et al 2013). Thus, enhancing noradrenergic receptor signaling may represent a useful approach for treatment of early cognitive impairment in AD (Chalermpalanupap et al 2013).…”

7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

“…Some of the positive TUNEL signals were not overlapped with MAP2 (white arrow), indicating that other cell types but not neurons were dead. It has been demonstrated that AD patients present with an early and prominent loss of LC neurons (Chalermpalanupap et al, 2013;Matthews et al, 2002;Weinshenker, 2008). Accordingly, we also tested the effect of 7,8-DHF on Ab-induced toxicity in LC neurons.…”

Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome

“…Targeted expression of genetically modified designer receptors exclusively activated by designer drugs (DREADDs) is an innovative tool that can be used to enhance neuronal activity (Vazey and Aston-Jones, 2014) and discrete neuronal populations (Clark et al, 2000;Nawaratne et al, 2008;Alexander et al, 2009;Pei et al, 2010). We used DREADDs in LC-NE neurons under control of the synthetic PRSx8 promoter for dopamine-␤ hydroxylase (DBH; Vazey and Aston-Jones, 2014) to limit distribution of the DREADDs to LC-NE neurons.…”