Xiang and colleagues previously showed that Aβ interacts with β2 adrenergic receptors (β2ARs), which could influence synaptic transmission and signaling. Aβ binding activates β2AR signaling as a partial agonist, but does not interfere with catecholamine binding. Acute treatment with Aβ leads to protein kinase A (PKA) activation, phosphorylation of AMPA receptor subunit 1 (GluR1), and an increase in mini-excitatory post-synaptic currents (mEPSCs). In this paper, they evaluated chronic, or persistent, effects of Aβ on β2AR signaling. They show that this treatment induces β2AR internalization, degradation, and a decrease in mEPSCs, suggesting an impairment of β2AR signaling. They show that levels of β2ARs are reduced in PS1 APP mice, suggesting that Aβ effects on β2AR could be contributing to impaired glutamatergic signaling in AD.
In human HEK293 cells, treatment with Aβ induced β2AR internalization and degradation, as did treatment with a β2AR agonist (isoproterenol), which worked faster and with greater magnitude. There was no comparable effect of Aβ on β1ARs, which do respond to isoproterenol. They then examined the effects of Aβ on primary neurons isolated from the prefrontal cortex. These neurons showed a similar Aβ-induced internalization of β2ARs, and a decreased response to stimulation with isoproterenol, including reduced cAMP production, lower PKA activation, reduced GluR1 phosphorylation, and reduced AMPA mediated mEPSCs.
Overall, this is a nicely carried out study showing that prolonged interactions of amyloid-β with β2ARs leads to impaired β2AR functionality. Demonstration of this phenomenon in primary neurons, and not just in HEK293 cells, strengthens the argument that this may be physiologically relevant, which is supported by their findings that β2AR levels are decreased in the PS1 APP mice. In addition to the damage occuring to the locus ceruleus (LC) noradrenergic neurons, the present paper suggests another means by which increased amyloid burden can perturb normal noradrenergic signaling. This also raises the possibility that amyloid-dependent changes in β2AR levels and signaling contribute to ongoing LC damage. For example, since the expression of neurotrophins, such as brain-derived neurotrophic factor and glial-derived neurotrophic factor, is regulated by cAMP levels, reduced β2AR signaling could lead to reduced neurotrophic support of LC neurons. Likewise, activation of β2AR is well known to reduce inflammatory responses of glial cells; therefore, reduced glial β2AR levels, which were not addressed in the current study, could potentially exacerbate inflammatory events.
This is a highly interesting paper that sheds further light on the fate of the noradrenergic system during the course of Alzheimer's disease. Central noradrenergic neurons, located in the locus ceruleus (LC), degenerate early in AD, and subsequently, norepinephrine (NE) levels decrease in LC projection areas. This paper by Wang and colleagues describes, in detail, β2 adrenoreceptor (β2AR) changes that occur in response to direct, N-terminal binding of Aβ to the β2AR, a phenomenon that has been previously found by the same authors. Now, sustained exposure to high Aβ levels in tissue, which may occur in AD due to either increased production in familial cases or reduced clearance in sporadic AD, induces internalization and degradation of the receptor. This, in turn, means that β2 adrenoceptor-mediated mechanisms may not only be impaired due to the already decreased NE levels, but also due to a decreased number of available receptor sides in LC projection areas. Evidence for this assumption comes from experiments that showed that a 40-minute Aβ pretreatment decreases the neuronal response upon β2AR agonist (isoproterenol) stimulation, including intracellular cAMP levels and PKA activity. Importantly, this effect limits PKA-dependent GluR1 phosphorylation and isoproterenol-evoked and AMPA receptor-mediated neuronal activity.
The current findings provide an explanation why β2 adrenoceptors are decreased in AD patient brains, in contrast to an expected increase in response to LC degeneration. Furthermore, they suggest that LC degeneration and Aβ binding to β2 adrenoceptors may act in concert to impair synaptic function in brain regions important to memory and cognition. We may be just beginning to understand the impact of these phenomena as mechanisms and drivers of disease. Further studies are warranted to identify suitable targets for intervention and reconstitution of the central noradrenergic system in AD.
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Univ of Illinois
Xiang and colleagues previously showed that Aβ interacts with β2 adrenergic receptors (β2ARs), which could influence synaptic transmission and signaling. Aβ binding activates β2AR signaling as a partial agonist, but does not interfere with catecholamine binding. Acute treatment with Aβ leads to protein kinase A (PKA) activation, phosphorylation of AMPA receptor subunit 1 (GluR1), and an increase in mini-excitatory post-synaptic currents (mEPSCs). In this paper, they evaluated chronic, or persistent, effects of Aβ on β2AR signaling. They show that this treatment induces β2AR internalization, degradation, and a decrease in mEPSCs, suggesting an impairment of β2AR signaling. They show that levels of β2ARs are reduced in PS1 APP mice, suggesting that Aβ effects on β2AR could be contributing to impaired glutamatergic signaling in AD.
In human HEK293 cells, treatment with Aβ induced β2AR internalization and degradation, as did treatment with a β2AR agonist (isoproterenol), which worked faster and with greater magnitude. There was no comparable effect of Aβ on β1ARs, which do respond to isoproterenol. They then examined the effects of Aβ on primary neurons isolated from the prefrontal cortex. These neurons showed a similar Aβ-induced internalization of β2ARs, and a decreased response to stimulation with isoproterenol, including reduced cAMP production, lower PKA activation, reduced GluR1 phosphorylation, and reduced AMPA mediated mEPSCs.
Overall, this is a nicely carried out study showing that prolonged interactions of amyloid-β with β2ARs leads to impaired β2AR functionality. Demonstration of this phenomenon in primary neurons, and not just in HEK293 cells, strengthens the argument that this may be physiologically relevant, which is supported by their findings that β2AR levels are decreased in the PS1 APP mice. In addition to the damage occuring to the locus ceruleus (LC) noradrenergic neurons, the present paper suggests another means by which increased amyloid burden can perturb normal noradrenergic signaling. This also raises the possibility that amyloid-dependent changes in β2AR levels and signaling contribute to ongoing LC damage. For example, since the expression of neurotrophins, such as brain-derived neurotrophic factor and glial-derived neurotrophic factor, is regulated by cAMP levels, reduced β2AR signaling could lead to reduced neurotrophic support of LC neurons. Likewise, activation of β2AR is well known to reduce inflammatory responses of glial cells; therefore, reduced glial β2AR levels, which were not addressed in the current study, could potentially exacerbate inflammatory events.
Klinik und Poliklinik für Neurologie
This is a highly interesting paper that sheds further light on the fate of the noradrenergic system during the course of Alzheimer's disease. Central noradrenergic neurons, located in the locus ceruleus (LC), degenerate early in AD, and subsequently, norepinephrine (NE) levels decrease in LC projection areas. This paper by Wang and colleagues describes, in detail, β2 adrenoreceptor (β2AR) changes that occur in response to direct, N-terminal binding of Aβ to the β2AR, a phenomenon that has been previously found by the same authors. Now, sustained exposure to high Aβ levels in tissue, which may occur in AD due to either increased production in familial cases or reduced clearance in sporadic AD, induces internalization and degradation of the receptor. This, in turn, means that β2 adrenoceptor-mediated mechanisms may not only be impaired due to the already decreased NE levels, but also due to a decreased number of available receptor sides in LC projection areas. Evidence for this assumption comes from experiments that showed that a 40-minute Aβ pretreatment decreases the neuronal response upon β2AR agonist (isoproterenol) stimulation, including intracellular cAMP levels and PKA activity. Importantly, this effect limits PKA-dependent GluR1 phosphorylation and isoproterenol-evoked and AMPA receptor-mediated neuronal activity.
The current findings provide an explanation why β2 adrenoceptors are decreased in AD patient brains, in contrast to an expected increase in response to LC degeneration. Furthermore, they suggest that LC degeneration and Aβ binding to β2 adrenoceptors may act in concert to impair synaptic function in brain regions important to memory and cognition. We may be just beginning to understand the impact of these phenomena as mechanisms and drivers of disease. Further studies are warranted to identify suitable targets for intervention and reconstitution of the central noradrenergic system in AD.
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