Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease.
Adrenergic beta-Antagonists
/ metabolism
Aging
/ physiology
Alzheimer Disease
/ metabolism
Animals
Brain
/ drug effects
Cognition
/ drug effects
Disease Models, Animal
Inflammation
/ drug therapy
Memory
/ drug effects
Mice
Mice, Transgenic
Microglia
/ metabolism
Norepinephrine
/ metabolism
Receptors, Adrenergic, beta
/ drug effects
Alzheimer's Disease
Behavior
Beta-adrenergic receptor
Beta-blocker
Lipopolysaccharide
Locus coeruleus
Neuroinflammation
Noradrenergic
Norepinephrine
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
15
04
2020
revised:
14
09
2020
accepted:
18
09
2020
pubmed:
25
9
2020
medline:
26
10
2021
entrez:
24
9
2020
Statut:
ppublish
Résumé
Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepinephrine (NE) neurons of the locus coeruleus (LC), which are vulnerable to age-related degeneration and are one of the earliest sites of pathology and degeneration in neurodegenerative disorders such as Alzheimer's Disease (AD). Loss of adrenergic tone may potentiate neuroinflammation both in aging and neurodegenerative conditions. Importantly, beta-blockers (beta-adrenergic antagonists) are a common treatment for hypertension, co-morbid with aging, and may further exacerbate neuroinflammation associated with loss of adrenergic tone in the central nervous system (CNS). The present studies were designed to both examine proinflammatory consequences of beta-blocker administration in an acute lipopolysaccharide (LPS) model as well as to examine chronic effects of beta-blocker administration on neuroinflammation and behavior in an amyloid-beta protein precursor (APP) mouse model of AD. We provide evidence for robust potentiation of peripheral inflammation with 4 different beta-blockers in an acute model of LPS. However, beta-blockers did not potentiate CNS inflammation in this model. Notably, in this same model, the genetic knockdown of either beta1- or beta2-adrenergic receptors in microglia did potentiate CNS inflammation. Furthermore, in an APP mouse model of amyloid pathology, chronic beta-blocker administration did potentiate CNS inflammation. The beta-blocker, metoprolol, also induced markers of phagocytosis and impaired cognitive behavior in both wild-type and APP mice. Given the induction of markers of phagocytosis in vivo, we examined phagocytosis of synaptosomes in an in vitro primary microglia culture and showed that beta-blockers enhanced whereas beta-adrenergic agonists inhibited phagocytosis of synaptosomes. In conclusion, beta-blockers potentiated inflammation peripherally in a systemic model of inflammation and centrally in an amyloidosis model of neuroinflammation. Additionally, beta-blockers impaired learning and memory and modulated synaptic phagocytosis with implications for synaptic degeneration. These findings warrant further consideration of the proinflammatory consequences of chronic beta-blocker administration, which are not restricted to the periphery in patients with neurodegenerative disorders.
Identifiants
pubmed: 32971233
pii: S0969-9961(20)30364-8
doi: 10.1016/j.nbd.2020.105089
pmc: PMC7686098
mid: NIHMS1635305
pii:
doi:
Substances chimiques
Adrenergic beta-Antagonists
0
Receptors, Adrenergic, beta
0
Norepinephrine
X4W3ENH1CV
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
105089Subventions
Organisme : NINDS NIH HHS
ID : P30 NS069375
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054533
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS097945
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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