Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.

The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.

Rhesus monkeys as a translational model for late-onset Alzheimer's disease.

Age is a major risk factor for late-onset Alzheimer's disease (AD) but seldom features in laboratory models of the disease. Furthermore, heterogeneity in size and density of AD plaques observed in individuals are not recapitulated in transgenic mouse models, presenting an incomplete picture. We show that the amyloid plaque microenvironment is not equivalent between rodent and primate species, and that differences in the impact of AD pathology on local metabolism and inflammation might explain established differences in neurodegeneration and functional decline. Using brain tissue from transgenic APP/PSEN1 mice, rhesus monkeys with age-related amyloid plaques, and human subjects with confirmed AD, we report altered energetics in the plaque microenvironment. Metabolic features included changes in mitochondrial distribution and enzymatic activity, and changes in redox cofactors NAD(P)H that were shared among species. A greater burden of lipofuscin was detected in the brains from monkeys and humans of advanced age compared to transgenic mice. Local inflammatory signatures indexed by astrogliosis and microglial activation were detected in each species; however, the inflamed zone was considerably larger for monkeys and humans. These data demonstrate the advantage of nonhuman primates in modeling the plaque microenvironment, and provide a new framework to investigate how AD pathology might contribute to functional loss.

An expanding GSK3 network: implications for aging research.

The last few decades of longevity research have been very exciting. We now know that longevity and healthspan can be manipulated across species, from unicellular eukaryotes to nonhuman primates, and that while aging itself is inevitable, how we age is malleable. Numerous dietary, genetic, and pharmacological studies now point to links between metabolism and growth regulation as a central aspect in determining longevity and, perhaps more importantly, health with advancing age. Here, we focus on a relatively new player in aging studies GSK3, glycogen synthase kinase, a key factor in growth and metabolism whose name fails to convey the extensive breadth of its role in cellular adaptation. First, we provide a brief overview of GSK3, touching on those aspects that are likely relevant to aging. Then, we outline the role of GSK3 in cellular functions including growth signaling, cell fate, and metabolism. Next, we describe evidence demonstrating a direct role for GSK3 in a range of age-related diseases, despite the fact that they differ considerably in their etiology and pathology. Finally, we discuss the role that GSK3 may play in normative aging and how GSK3 might be a suitable target to oppose age-related disease vulnerability.

GSK3ß Regulates Brain Energy Metabolism.

GSK3ß is a serine threonine kinase implicated in the progression of Alzheimer's disease. Although the role of GSK3ß in growth and pathology has been extensively studied, little is known about the metabolic consequences of GSK3ß manipulation, particularly in the brain. Here, we show that GSK3ß regulates mitochondrial energy metabolism in human H4 neuroglioma cells and rat PC12-derived neuronal cells and that inhibition of GSK3ß in mice in vivo alters metabolism in the hippocampus in a region-specific manner. We demonstrate that GSK3ß inhibition increases mitochondrial respiration and membrane potential and alters NAD(P)H metabolism. These metabolic effects are associated with increased PGC-1α protein stabilization, enhanced nuclear localization, and increased transcriptional co-activation. In mice treated with the GSK3ß inhibitor lithium carbonate, changes in hippocampal energy metabolism are linked to increased PGC-1α. These data highlight a metabolic role for brain GSK3ß and suggest that the GSK3ß/PGC-1α axis may be important in neuronal metabolic integrity.