Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease

Abstract

Currently, there are no available approaches to cure or slow down the progression of Alzheimer’s disease (AD), which is characterized by the accumulation of extracellular amyloid-β (Aβ) deposits and intraneuronal tangles composed of hyperphosphorylated tau. β2 adrenergic receptors (β2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to Alzheimer’s disease; however these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent beta-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here we show that administration of ICI 118,551, a selective β2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI 118,551 increased Aβ levels and Aβ plaque burden. Concomitantly, ICI 118,551-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic APP processing. These results suggest that under the conditions used here, selective pharmacological inhibition of β2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between β2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of beta-blockers on AD.

Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening

“…The tau-lowering effects of moxonidine and metaproterenol were abolished by their corresponding antagonists atipomezole and propranol, which elevated tau levels by themselves. In agreement with our findings, the selective β2-AR antagonist ICI 118,551 increased tau phosphorylation and accumulation in an AD mouse model ( Branca et al., 2014 ). Paradoxically, genetic suppression of β2-ARs reduced tau pathology ( Wisely et al., 2014 ).…”

Dyrk1 inhibition improves Alzheimer's disease‐like pathology

“…Brains were processed as previously described (Branca et al ., ). Briefly, hemibrains were drop fixed in 4% paraformaldehyde in phosphate‐buffered saline for 48 h and then transferred into 0.02% sodium azide in phosphate‐buffered saline until slicing; 50‐μm‐thick free‐floating sections were subsequently obtained using a vibratome.…”

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist

“…Many of these deficits are reversed with NA or NA precursor supplementation. Additionally, pharmacological blockade of beta-adrenergic receptors in a mouse model of AD has been shown to exacerbate cognitive deficits and neuroinflammation and to increase amyloid beta and plaque loads (Branca et al 2014). …”