Norepinephrine Protects against Amyloid-β Toxicity via TrkB

Abstract

The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer’s disease. Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor (BDNF). Here, we report that NE dosedependently protected primary cortical and LC neurons from amyloid-β (Aβ) toxicity. The neuroprotective effects of NE were fully prevented by the Trk receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against Aβ toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease.

Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

“…Moreover, NE-dependent modulation of long-term alterations in synaptic strength and gene transcription, particularly within the hippocampus and prefrontal cortex, influences memory formation and experience-dependent alterations in neural function and behavior and plays a critical role in the ability of the LC to optimize performance [105]. Finally, evidence from transgenic mouse models of AD and neuronal cell culture studies show that NE exerts a wide array of neuroprotective effects including anti-inflammatory and pro-neurotrophic mechanisms [32, 43, 44, 58, 64, 72, 74, 117]. Taken together, these data suggest that the central NE projection system is essential for cognitive function and, in turn, that LC neuronal degeneration contributes to cognitive dysfunction.…”

Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system

“…), and reduces Aβ‐dependent damage in primary cortical neuronal cultures (Counts and Mufson ; Liu et al . ). Interestingly, in the latter studies, the neuroprotection due to NA was reduced by a selective antagonist of tropomyosin receptor kinase B (TrkB), the receptor for brain‐derived neurotrophic factor (BDNF), suggesting that the effects of NA can involve induction of TrkB:BDNF signaling (Liu et al .…”

“…Interestingly, in the latter studies, the neuroprotection due to NA was reduced by a selective antagonist of tropomyosin receptor kinase B (TrkB), the receptor for brain‐derived neurotrophic factor (BDNF), suggesting that the effects of NA can involve induction of TrkB:BDNF signaling (Liu et al . ). In primary rat hippocampal neurons, treatment with NA, as well as with an NO donor, increased cell survival in the context of nutrient depletion (Patel et al .…”

The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain

“…Increasing NE levels improved cognition in aging rats [34] and in transgenic mice models of Alzheimer’s disease [35, 36]. In vitro, NE administration promoted growth factors and provided protection against β-amyloid toxicity by an adrenergic-receptor-independent route [37]. Consistent with this protective role of NE, damaging the LC in transgenic Alzheimer’s disease model mice increased cortical and hippocampal neuroinflammation and β-amyloid deposition [38].…”