Publications by authors named "Amanda Rubin"

6 Publications

  • Page 1 of 1

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

Nature 2021 Feb 20;590(7844):122-128. Epub 2021 Jan 20.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease. Systemically, circulating pro-inflammatory factors can promote cognitive decline, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E (PGE), a major modulator of inflammation. In ageing macrophages and microglia, PGE signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
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http://dx.doi.org/10.1038/s41586-020-03160-0DOI Listing
February 2021

NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.

J Exp Med 2017 06 25;214(6):1711-1724. Epub 2017 Apr 25.

S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4 T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8 T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3 hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
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http://dx.doi.org/10.1084/jem.20161707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461004PMC
June 2017

Microglial malfunction: the third rail in the development of Alzheimer's disease.

Trends Neurosci 2015 Oct;38(10):621-636

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Institute, Stanford, CA, USA. Electronic address:

Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-β (Aβ) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Aβ accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Aβ pathology.
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http://dx.doi.org/10.1016/j.tins.2015.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670239PMC
October 2015

Nurses as Champions for Patient Safety and Interdisciplinary Problem Solving.

Medsurg Nurs 2015 Mar-Apr;24(2):107-10

Nurses on an inpatient surgical unit were apprehensive in activating the Rapid Response Team (RRT). Nurse-led interdisciplinary solutions addressed perceived barriers and led to open communication and issue resolution with physician colleagues.
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September 2015

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior.

Proc Natl Acad Sci U S A 2012 Jul 25;109(28):11360-5. Epub 2012 Jun 25.

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.

A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.
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http://dx.doi.org/10.1073/pnas.1209293109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396525PMC
July 2012

The progesterone-induced enhancement of object recognition memory consolidation involves activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways in the dorsal hippocampus.

Horm Behav 2012 Apr 13;61(4):487-95. Epub 2012 Jan 13.

Department of Psychology, Yale University, New Haven, CT 06520, USA.

Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17β-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory consolidation in young ovariectomized female mice (Orr et al., 2009). The goal of the present study was to identify the biochemical alterations that might underlie this mnemonic enhancement. We hypothesized that the P-induced enhancement of object recognition would be dependent on activation of the ERK and mTOR pathways. In young ovariectomized mice, we found that bilateral dorsal hippocampal infusion of P significantly increased levels of phospho-p42 ERK and the mTOR substrate S6K in the dorsal hippocampus 5 min after infusion. Phospho-p42 ERK levels were downregulated 15 min after infusion and returned to baseline 30 min after infusion, suggesting a biphasic effect of P on ERK activation. Dorsal hippocampal ERK and mTOR activation were necessary for P to facilitate memory consolidation, as suggested by the fact that inhibitors of both pathways infused into the dorsal hippocampus immediately after training blocked the P-induced enhancement of object recognition. Collectively, these data provide the first demonstration that the ability of P to enhance memory consolidation depends on the rapid activation of cell signaling and protein synthesis pathways in the dorsal hippocampus.
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http://dx.doi.org/10.1016/j.yhbeh.2012.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401043PMC
April 2012