Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

Rapid and reversible methods for altering the level of endogenous proteins are critically important for studying biological systems and developing therapeutics. Here, we describe a membrane permeable targeting peptide-based method that rapidly and reversibly knocks down endogenous proteins through chaperone-mediated autophagy in vitro and in vivo. We demonstrated the specificity, efficacy and generalizability of the method by showing efficient knockdown of various proteins including death associated protein kinase 1 (160kDa), scaffolding protein PSD-95 (95kDa) and α-synuclein (18kDa) with their respective targeting peptides in a dose-, time- and lysosomal activity-dependent manner in neuronal cultures. More significantly, we showed that when given systemically, the peptide system efficiently knocked down the targeted protein in the brain of intact rats. Our study provides a robust and convenient research tool to manipulate endogenous protein levels, and may also lead to the development of protein knockdown-based novel therapeutics for treating various human diseases.

The past two decades have seen remarkable progress in our understanding of the multifactorial drivers of hippocampal aging and cognitive decline. Recent findings have also raised the possibility of functional rejuvenation in the aged hippocampus. In this review, we aim to synthesize the mechanisms that drive hippocampal aging and evaluate critically the potential for rejuvenation. We discuss the functional changes in synaptic plasticity and regenerative potential of the aged hippocampus, followed by mechanisms of microglia aging, and assess the cross talk between these proaging processes. We then examine proyouth interventions that demonstrate significant promise in reversing age-related impairments in the hippocampus and, finally, attempt to look ahead toward novel therapeutics for brain aging.

The N-methyl-D-aspartate receptors (NMDARs) are part of a large multiprotein complex at the glutamatergic synapse. The assembly of NMDARs with synaptic proteins offers a means to regulate NMDAR channel properties and receptor trafficking, and couples NMDAR activation to distinct intracellular signaling pathways, thus contributing to the versatility of NMDAR functions. Receptor-protein interactions at the synapse provide a dynamic and powerful mechanism for regulating synaptic efficacy, but can also contribute to NMDAR overactivation-induced excitotoxicity and cellular damage under pathological conditions. An emerging concept is that by understanding the mechanisms and functions of disease-specific protein-protein interactions in the NMDAR complex, we may be able to develop novel therapies based on protein-NMDAR interactions for the treatment of brain diseases in which NMDAR dysfunction is at the root of their pathogenesis.

Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc–specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson’s disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-βsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-βsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-βsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-βsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.

Rapid and reversible methods for altering the function of endogenous proteins are not only indispensable tools for probing complex biological systems, but may potentially drive the development of new therapeutics for the treatment of human diseases. Genetic approaches have provided insights into protein function, but are limited in speed, reversibility and spatiotemporal control. To overcome these limitations, we have developed a peptide‐based method (SNIPER: Selective Native Protein Eradication) to degrade any given endogenous protein at the post‐translational level by harnessing chaperone‐mediated autophagy, a major intracellular protein degradation pathway. This unit presents a typical strategy in the design and validation of a protein‐knockdown peptide. © 2015 by John Wiley & Sons, Inc.

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