Aβ oligomers may set off tau phosphorylation by hijacking the adrenergic system, according to a study published January 15 in Science Translational Medicine. Researchers led by Qin Wang at the University of Alabama in Birmingham reported that Aβ oligomers bind to the α2A-adrenergic receptor. This not only sensitized the receptor to its ligand, norepinephrine, but also rejiggered the downstream signaling cascade to include activation of a new substrate, GSK-3β, a kinase that phosphorylates tau. The researchers reported that blocking α2AAR signaling in mouse models of amyloidosis effectively nipped Aβ toxicity in the bud—dousing neuroinflammation, reducing tau hyperphosphorylation, and even preventing memory loss. All this occurs at one hundredth the concentration of Aβ needed to induce GSK-3β in cells lacking α2AAR.
- In mice, Aβ oligomers bind α2A adrenergic receptors.
- This triggers GSK-3β activation, and tau phosphorylation.
- Blocking α2AARs reduced p-tau, Aβ plaques, and memory loss.
“This elegant study provides a possible pathway to explain the interaction between Aβ and hyperphosphorylated tau in the pathogenesis and progression of Alzheimer’s disease,” commented Lea Grinberg of the University of California, San Francisco. “Modulation of this pathway has the potential to slow down AD progression, if the same mechanism proves to be relevant to AD in humans.”
Produced by neurons in the locus coeruleus (LC)—a tiny kernel nestled deep within the brainstem—the neurotransmitter norepinephrine sharpens attention, arousal, cognition, and responses to stress. NE orchestrates all this by binding to a variety of adrenergic receptors expressed in the LC and elsewhere in the brain. In AD, LC neurons are among the first afflicted by tau pathology and start to wither early in the disease (Braak et al., 2011; Weinshenker, 2018; Kelly et al., 2017).
Researchers have attributed agitation, aggression, and psychosis in people with AD to surviving LC neurons that overcompensate for the loss of their brethren by ramping up adrenergic signaling (Herrmann et al., 2004). Damage to the LC may accelerate AD progression, since previous studies have demonstrated that loss of LC neurons exacerbates Aβ deposition, neuroinflammation, and memory loss in mice (Dec 2010 webinar).
First authors Fang Zhang and Mary Gannon investigated the potential role of one subfamily of adrenergic receptors in AD—α2AAR. These G-protein-coupled receptors are expressed in several organs, including the brain. Agonists trigger a range of responses including sleepiness, low blood pressure, and improved cognition (Cottingham et al., 2011).
To discern if α2AAR signaling went haywire in AD, the researchers measured α2AAR signaling in membrane extracts from postmortem brain samples of 15 people with AD versus 15 controls. In the former, α2AAR were abnormally sensitive, as gauged by the amount of NE required to set off G protein activation. Sifting through the National Alzheimer’s Coordinating Center database, Zhang and colleagues also found that the α2AAR agonist clonidine worsened cognition in people with dementia. This hypertension drug did not tax cognition in healthy people. Together, the findings hinted that hyperactive α2AAR receptors might exacerbate AD.
The researchers next looked for α2AAR shenanigans in mice. They found that it took about 20-fold less NE to stimulate α2AAR signaling—as measured by G protein activation—in cells from APP/PS1 mice than in cells from non-transgenic mice, despite similar receptor levels. Cells from APP knock-ins also had slightly more sensitive receptors than controls. Similarly, adding synthetic Aβ42 oligomers to cell membrane preparations from wild-type mice boosted sensitivity of the receptor to NE, as did extracts of soluble matter from AD brain. Together, the findings suggested that Aβ oligomers somehow lower the threshold for NE activation of α2AAR signaling.
To find out how Aβ boosts NE signaling, the researchers ran biochemical, genetic, and structural experiments. They found that Aβ oligomers bound to an allosteric site on the α2AA receptor, distinct from its NE binding site. This changed the signaling cascade, leading to phosphorylation of new target proteins. From a kinase screen, the researchers found that one was GSK-3β.
Not only did Aβ enhance NE-mediated G protein activation, NE signaling enhanced Aβ activation of GSK3β as well. When added with clonidine to cultured neurons, just 20 nM Aβ oligomers activated GSK3β—less than 1 percent of the Aβ concentration previously reported to activate GSK3β (Jo et al., 2011; Kirouac et al., 2017). In the absence of clonidine, Zhang found no activation of GSK-3β by up to 100 nM Aβ. These findings suggest that α2AAR signaling dramatically enhanced the potency of Aβ to set off GSK-3β activation and tau phosphorylation, at least in vitro.
Adrenergic Hijacking? Norepinephrine (NE) activates normal α2AAR signaling (1). Aβ redirects α2AAR to activate GSK-3β, which phosphorylates tau (2). Idazoxan, an α2AAR antagonist, blocks the cascade (3). [Courtesy of Zhang et al., Science Translational Medicine, 2020.]
Next, the researchers injected Aβ oligomers into the brains of non-transgenic mice, with or without blocking GSK-3β or α2AARs. On their own, Aβ oligomers activated GSK-3β, resulting in tau hyperphosphorylation in the hippocampus. In the presence of lithium, a GSK-3β inhibitor, or idazoxan, an α2AAR blocker, both GSK-3β activation and tau hyperphosphorylation were curbed. The findings implicated the adrenergic pathway in the instigation of tau hyperphosphorylation by Aβ oligomers.
Would blocking α2AAR signaling stave off disease in mice with amyloidosis? Indeed, treating plaque-ridden 7.5-month-old APP/PS1 mice with idazoxan for eight weeks reversed GSK-3β hyperactivation and lowered the burden of hyperphosphorylated tau “pretangles,” i.e., phospho-tau clusters in Aβ plaque-laden areas. These mice do not develop the fibrillar tau tangles observed in people with AD. Idazoxan-treated mice had roughly 30 percent less phospho-tau per area of Aβ than control mice did (see image below). The α2AAR blocker also curbed Aβ plaque burden, and lowered the density of Iba1-positive microglia, suggesting it reduced neuroinflammation. The treatment had similar effects in APP knock-in animals.
Finally, the researchers found that idazoxan treatment spared APP/PS1 mice from spatial memory loss. In APP knock-ins, which are slow to retreat to dark, hidden areas when placed in more environs, idazoxan restored their reticence.
Wang told Alzforum that the findings not only mechanistically link Aβ to tau pathology, but also support the idea that adrenergic signaling promotes Aβ accumulation. This is in keeping with a previous study that linked GSK-3β activation to Aβ production, as well as one that found adrenergic signaling disrupts proper trafficking of APP by sorting receptors (Chen et al., 2014; Ly et al., 2013).
To Wang’s mind, the potency of Aβ oligomers in activating GSK3β via the adrenergic cascade implies that tau pathology starts early in AD, perhaps even before amyloid shows up on PET scans. This is in keeping with recent CSF biomarker data that detected an uptick in p-tau at the earliest stages of AD (Aug 2019 news).
Virgil Muresan of Rutgers University, Newark, New Jersey, proposed more than a decade ago that the Aβ cascade starts out in the LC. He wrote that the findings explain why the region is also host to the earliest accumulation of tau (Muresan and Muresan, 2008). “The paper does not address what is the primary event that initiates AD, i.e., where the initial pool of Aβ oligomers—even infinitesimal in amount—comes from,” Muresan added, though his previous studies suggest that LC neurons release copious amounts of Aβ oligomers.
The low concentration of Aβ oligomers required to set the tau cascade in motion could explain why Aβ-targeted therapies have so far failed to dramatically slow cognitive decline in people with AD, Wang said. Immunotherapies would be hard-pressed to lower Aβ concentrations into the nanomolar range required to prevent Aβ oligomerization, especially since Aβ commonly reaches micromolar levels in the AD brain. Wang believes adding an α2AAR blocker such as idazoxan might make Aβ-targeted therapies more effective. Idazoxan has been tested in clinical trials for depression, schizophrenia, and progressive supranuclear palsy (Litman et al., 1996; Ghika et al., 1991).
“This study represents an important advance in the field, particularly given the rigor of the experiments,” commented David Weinshenker of Emory University School of Medicine in Atlanta. “Moreover, identification of the α2AAR as a mediator of Aβ oligomer-triggered tau pathology provides a new target for Alzheimer’s disease pharmacotherapies.” However, Weinshenker cautioned that α2AAR antagonists block all α2AAR transmission throughout the body and have cardiovascular and anxiogenic effects. More detailed structural knowledge of Aβo-α2AAR binding could aid in the development of therapeutic molecules to block the interaction between the two molecules, while leaving normal α2AAR signaling intact, he said. Wang is running screens in search of just such a compound.
Khalid Iqbal of the New York State Institute for Basic Research in Staten Island wondered how to reconcile the study’s findings with the fact that about 30 percent of aged people have significant brain amyloid accumulation, but no clinical symptoms of AD. “Either there is some mechanism overriding that reported in this study in the human brain, or the findings are limited to transgenic mouse models used,” he wrote.—Jessica Shugart
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