Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease

Evans, Andrew K.; Ardestani, Pooneh Memar; Yi, B; Park, Heui Hye; Lam, Rachel; Shamloo, Mehrdad

doi:10.1016/j.nbd.2020.105089

Cited by 56 publications

(53 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, we assessed safety and tolerability of acute exposure to our novel chemicals through the following sequence of tests immediately following IP injection: maximum tolerated dose with novel cage observation at 100, 300, or 900 mg/kg, and then SHIRPA, activity chamber, and then hot plate latency using 100 or 30 mg/kg IP in different drug naïve mice. Second, we investigated the impact of chronic exposure to 10 mg/kg (3-times lower dose than that with minimal acute impact on locomotor activity) daily IP injection starting one week prior to assessment of locomotion in the activity chamber and elevated plus maze (week 1), or learning and memory with Y maze (week 2), Morris water maze (weeks 2 and 3), and then fear conditioning (week 4) according to established protocols 25 – 30 , including not counterbalancing the escape platform location 68 , 69 . Animals were dosed daily from 3 to 5 PM after the conclusion of each behavioral testing session.…”

Section: Methodsmentioning

confidence: 99%

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Wawro

Gajera

Baker

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln.

show abstract

Section: Methodsmentioning

confidence: 99%

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Wawro

Gajera

Baker

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, exposing microglia deriving from either n-3 deficient or n-3 sufficient mice to pHrodo labeled SYN, the authors showed that the lack of n-3 from microglia increases the phagocytic capacity of microglial cells, inducing an excessive synaptic loss ( 148 ). Recently, Evans et al, exploited pHrodo labeled SYNs in order to show that beta-adrenergic antagonists, such as metropolol, are able to significantly increase phagocytosis of primary microglia from rats, whereas beta-adrenergic agonists, such as xamoterol and isoproterenol, attenuate SYNs engulfment ( 149 ). SYNs labeled with pH sensitive dyes have been also exploited to investigate the engulfment capacity of astrocytes ( 147 ), which supported astrocyte critical role not only in trophic functions and neurotransmitters recycling, but also in synapse elimination pruning ( 150 ).…”

Section: In Vitro and Ex Vivo Engulfmentmentioning

confidence: 99%

Strategies and Tools for Studying Microglial-Mediated Synapse Elimination and Refinement

et al. 2021

View full text Add to dashboard Cite

The role of microglia in controlling synapse homeostasis is becoming increasingly recognized by the scientific community. In particular, the microglia-mediated elimination of supernumerary synapses during development lays the basis for the correct formation of neuronal circuits in adulthood, while the possible reactivation of this process in pathological conditions, such as schizophrenia or Alzheimer's Disease, provides a promising target for future therapeutic strategies. The methodological approaches to investigate microglial synaptic engulfment include different in vitro and in vivo settings. Basic in vitro assays, employing isolated microglia and microbeads, apoptotic membranes, liposomes or synaptosomes allow the quantification of the microglia phagocytic abilities, while co-cultures of microglia and neurons, deriving from either WT or genetically modified mice models, provide a relatively manageable setting to investigate the involvement of specific molecular pathways. Further detailed analysis in mice brain is then mandatory to validate the in vitro assays as representative for the in vivo situation. The present review aims to dissect the main technical approaches to investigate microglia-mediated phagocytosis of neuronal and synaptic substrates in critical developmental time windows.

show abstract

“…Interestingly, chronic administration of this beta-blocker enhanced peripheral and central inflammation. This suggests that chronic application of beta blockers in AD should be carefully considered because of its potential inflammatory reaction in the brain [ 103 ]. Collectively, these studies highlight the role of ARs in learning and memory and their potential to act as therapeutic targets for treatment of AD.…”

Section: Norepinephrine Adrenergic System and Alzheimer’s Diseasementioning

confidence: 99%

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease

Bekdash

2021

IJMS

View full text Add to dashboard Cite

Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer’s disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer’s disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer’s disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer’s disease and potential therapeutic implications.

show abstract

Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease

Cited by 56 publications

References 49 publications

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Strategies and Tools for Studying Microglial-Mediated Synapse Elimination and Refinement

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease

Contact Info

Product

Resources

About