Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner.

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD), and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression. Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid-beta and tau oligomers, two major pathological effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner.

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.

Mitochondrial Calcium Transport During Autophagy Initiation.

While it has been shown that Ca dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types.

A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.

Dysregulated iron or Ca homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca overflow, through an interaction of Fe with mitochondrial calcium uniporter (MCU).

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.