Dataset Information

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

ABSTRACT: As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

SUBMITTER: Villeda SA

PROVIDER: S-EPMC4224436 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

Villeda Saul A SA Plambeck Kristopher E KE Middeldorp Jinte J Castellano Joseph M JM Mosher Kira I KI Luo Jian J Smith Lucas K LK Bieri Gregor G Lin Karin K Berdnik Daniela D Wabl Rafael R Udeochu Joe J Wheatley Elizabeth G EG Zou Bende B Simmons Danielle A DA Xie Xinmin S XS Longo Frank M FM Wyss-Coray Tony T

Nature medicine 20140504 6

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are c ...[more]

PMID: 24793238

Similar Datasets

Project description:Chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans (PGs) are major extracellular matrix (ECM) components of the central nervous system (CNS). A large body of evidence has shown that CSPGs/DSPGs play critical roles in neuronal growth, axon guidance, and plasticity in the developing and mature CNS. It has been proposed that these PGs exert their function through specific interaction of CS/DS chains with its binding partners in a manner that depends on the sulfation patterns of CS/DS. It has been reported that dermatan 4-O-sulfotransferase-1 (Chst14/D4st1) specific for DS, but not chondroitin 4-O-sulfotransferase-1 (Chst11/C4st1) specific for CS, regulates proliferation and neurogenesis of neural stem cells (NSCs), indicating that CS and DS play distinct roles in the self-renewal and differentiation of NSCs. However, it remains unknown whether specific sulfation profiles of DS has any effect on CNS plasticity. In the present study, Chst14/D4st1-deficient (Chst14 -/-) mice was employed to investigate the involvement of DS in synaptic plasticity. First, behavior study using Morris Water Maze (MWM) showed that the spatial learning and memory of Chst14 -/- mice was impaired when compared to their wild type (WT) littermates. Corroborating the behavior result, long-term potentiation (LTP) at the hippocampal CA3-CA1 connection was reduced in Chst14 -/- mice compared to the WT mice. Finally, the protein levels of N-Methyl-D-aspartate (NMDA) receptor, ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, postsynaptic density 95 (PSD95), growth associated protein 43 (GAP-43), synaptophysin (SYN) and N-ethylmaleimide sensitive factor (NSF) which are important in synaptic plasticity were examined and Chst14/D4st1 deficiency was shown to significantly reduce the expression of these proteins in the hippocampus. Further studies revealed that Akt/mammalian target rapamycin (mTOR) pathway proteins, including protein kinase B (p-Akt), p-mTOR and p-S6, were significantly lower in Chst14 -/- mice, which might contribute to the decreased protein expression. Together, this study reveals that specific sulfation of DS is critical in synaptic plasticity of the hippocampus and learning and memory, which might be associated with the changes in the expression of glutamate receptors and other synaptic proteins though Akt/mTOR pathway.

Project description:Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer's disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer's disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism.Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-?B p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-?B p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine.Galantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?), and NF-?B p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-?B p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-?B p65 levels as well as expression of pro-inflammatory cytokines (IL-1?, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line.These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.

Dataset Information

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

Publications

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets