Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease
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 degeneratio...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120303648 |
| _version_ | 1818610560452788224 |
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| author | Andrew K. Evans Pooneh M. Ardestani Bitna Yi Heui Hye Park Rachel K. Lam Mehrdad Shamloo |
| author_facet | Andrew K. Evans Pooneh M. Ardestani Bitna Yi Heui Hye Park Rachel K. Lam Mehrdad Shamloo |
| author_sort | Andrew K. Evans |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T15:16:23Z |
| format | Article |
| id | doaj.art-aa54e9dbb4614cb9b0f954cfa4a041d1 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T15:16:23Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-aa54e9dbb4614cb9b0f954cfa4a041d12022-12-21T22:26:47ZengElsevierNeurobiology of Disease1095-953X2020-12-01146105089Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's DiseaseAndrew K. Evans0Pooneh M. Ardestani1Bitna Yi2Heui Hye Park3Rachel K. Lam4Mehrdad Shamloo5Department of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304, United States of AmericaDepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304, United States of AmericaDepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304, United States of AmericaDepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304, United States of AmericaDepartment of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304, United States of AmericaCorresponding author.; Department of Neurosurgery, Stanford University School of Medicine, 1050 Arastradero Road, Building A, Palo Alto, CA 94304, United States of AmericaAdrenergic 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.http://www.sciencedirect.com/science/article/pii/S0969996120303648Alzheimer's DiseaseNoradrenergicNorepinephrineLocus coeruleusBeta-adrenergic receptorBeta-blocker |
| spellingShingle | Andrew K. Evans Pooneh M. Ardestani Bitna Yi Heui Hye Park Rachel K. Lam Mehrdad Shamloo Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease Neurobiology of Disease Alzheimer's Disease Noradrenergic Norepinephrine Locus coeruleus Beta-adrenergic receptor Beta-blocker |
| title | Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease |
| title_full | Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease |
| title_fullStr | Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease |
| title_full_unstemmed | Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease |
| title_short | Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease |
| title_sort | beta adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of alzheimer s disease |
| topic | Alzheimer's Disease Noradrenergic Norepinephrine Locus coeruleus Beta-adrenergic receptor Beta-blocker |
| url | http://www.sciencedirect.com/science/article/pii/S0969996120303648 |
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