Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.

Recent studies demonstrate that Parkinson's disease (PD) is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B deficiency.

Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e.

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model.

Introduction: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction.

Methods: PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APP) and wild-type controls.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear.

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation.

Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria.

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

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.

The Dueling Duo: IL10 and TNF Face Off in Microglial Recovery from Endotoxin Challenge.

The molecular mechanisms that restore microglial quiescence after acute stimulation remain largely unexplored, unlike those that drive microglial activation. In this issue of Immunity, Shemer et al. discover that the microglial IL-10 receptor counteracts the pro-inflammatory effects of TNF to allow restoration of microglial quiescence after peripheral endotoxin challenge.

Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau.

Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy.

Background: Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target.

Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer's disease related pathology.

Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer's Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD.

Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration.

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu.

Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11bCD45 myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11bCD45 cells trafficking to ischemic brain.

Revisiting IDO and its value as a predictive marker for anti-PD-1 resistance.

Botticelli et al. proposed the activity of indoleamine-2,3-dioxygenase 1 (IDO) as a potential mechanism and predictive marker for primary resistance against anti-PD-1 treatment in the context of non-small cell lung cancer. However, there are a few points for the authors to address in order to strengthen their claims.

Macrophage de novo NAD synthesis specifies immune function in aging and inflammation.

Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD derives substantially from KP metabolism of tryptophan.

Immersion medicine programme for secondary students.

Background: Although the proportion of ethnicities representing under-represented minorities in medicine (URM) in the general population has significantly increased, URM enrolment in medical schools within the USA has remained stagnant in recent years.

Methods: This study sought to examine the effect of an immersion in community medicine (ICM) programme on secondary school students' desire to enter the field of medicine and serve their communities. The authors asked all 69 ICM alumni to complete a 14-question survey consisting of six demographic, four programme and four career questions, rated on a Likert scale of 1 (completely disagree) to 5 (completely agree), coupled with optional free-text questions.

The effects of passive and active learning on student preference and performance in an undergraduate basic science course.

Active learning is based on self-directed and autonomous teaching methods, whereas passive learning is grounded in instructor taught lectures. An animal physiology course was studied over a two-year period (Year 1, n = 42 students; Year 2, n = 30 students) to determine the effects of student-led seminar (andragogical) and lecture (pedagogical) teaching methods on students' retention of information and performance. For each year of the study, the course was divided into two time periods.