title: 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 that comprised hyperphosphorylated tau. The 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 AD; 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 β-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 (ICI), a selective β2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased Aβ levels and Aβ plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic 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 β blockers on AD.
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, USA; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Branca
authors.affiliation: Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Wisely
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Hartman
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, USA; Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caccamo
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, USA; Department of Basic Medical Sciences, University of Arizona College of Medicine at Phoenix, Phoenix, AZ, USA. Electronic address: oddo@email.arizona.edu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003071:Cognition; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D011412:Propanolamines / Q000008:administration & dosage / Q000009:adverse effects*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D016229:Amyloid beta-Peptides; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D016875:tau Proteins; C026777:ICI 118551
keywords: APP; Aβ; Tangles; tau; β Blockers