Restoring the pattern of proteoglycan sulphation in perineuronal nets corrects age-related memory loss

AbstractMemory loss is a usual consequence of ageing and aged mice show progressive deficits in memory tasks. In aged brains, perineuronal nets (PNNs), which are implicated in plasticity and memory, become inhibitory due to decreased 6-sulphation of their glycan chains (C6S). Removal of PNNs or digestion of their glycosaminoglycans rescued age-related memory loss. Premature reduction of permissive C6S by transgenic deletion of chondroitin 6-sulfotransferase led to very early memory loss. However, restoring C6S levels in aged animals by AAV delivery or transgenic expression of 6-sulfotransferase restored memory. Low C6S levels caused loss of cortical long-term potentiation, which was restored by AAV-mediated 6-sulfotransferase delivery. The study shows that loss of C6S in the aged brain leads to declining memory and cognition. Age-related memory impairment was restored by C6S replacement or other interventions targeting perineuronal nets

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Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

Molecular Psychiatry ◽

10.1038/s41380-021-01208-9 ◽

2021 ◽

Author(s):

Sujeong Yang ◽

Sylvain Gigout ◽

Angelo Molinaro ◽

Yuko Naito-Matsui ◽

Sam Hilton ◽

...

Keyword(s):

Chondroitin Sulphate ◽

Memory Loss ◽

Memory Deficits ◽

Long Term Potentiation ◽

Aged Mice ◽

Age Related ◽

Term Potentiation ◽

Early Memory

AbstractPerineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

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Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses

Scientific Reports ◽

10.1038/s41598-019-56133-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Marta Maglione ◽

Gaga Kochlamazashvili ◽

Tobias Eisenberg ◽

Bence Rácz ◽

Eva Michael ◽

...

Keyword(s):

Molecular Basis ◽

Memory Impairment ◽

Mossy Fiber ◽

Long Term Potentiation ◽

Age Related ◽

Term Potentiation ◽

Hippocampal Synapses ◽

Age Dependent ◽

Age Related Changes

AbstractAging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine.

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Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1514486112 ◽

2015 ◽

Vol 112 (36) ◽

pp. E5078-E5087 ◽

Cited By ~ 59

Author(s):

G. Aleph Prieto ◽

Shikha Snigdha ◽

David Baglietto-Vargas ◽

Erica D. Smith ◽

Nicole C. Berchtold ◽

...

Keyword(s):

Memory Impairment ◽

Long Term Potentiation ◽

Neuronal Cultures ◽

Receptor Subunit ◽

Age Related ◽

Term Potentiation ◽

Hippocampal Synapses ◽

Receptor Domain

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1β (IL-1β). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1β impairment. In hippocampal neuronal cultures, IL-1β increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1β. To evaluate whether synapses develop a similar heightened sensitivity to IL-1β with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1β impairs LTP directly at the synapse and that sensitivity to IL-1β is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1β was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1β levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1β. Accordingly, selective blocking of AcP-dependent signaling with Toll–IL-1 receptor domain peptidomimetics prevented IL-1β–mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1β that occurs with age.

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Inhibition of c-Jun N-terminal kinase decelerates the reversal of induced long-term potentiation: implication on treatment of memory loss

10.26226/morressier.5b681765b56e9b005965c27b ◽

2018 ◽

Author(s):

Marwa Yousef

Keyword(s):

Memory Loss ◽

Long Term Potentiation ◽

Term Potentiation

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Progressive Age-Related Impairment of the Late Long-Term Potentiation in Alzheimer's Disease Presenilin-1 Mutant Knock-in Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-2010-1302 ◽

2010 ◽

Vol 19 (3) ◽

pp. 1021-1033 ◽

Cited By ~ 29

Author(s):

Alexandra Auffret ◽

Vanessa Gautheron ◽

Mark P. Mattson ◽

Jean Mariani ◽

Catherine Rovira

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Long Term Potentiation ◽

Presenilin 1 ◽

Age Related ◽

Term Potentiation

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LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent

eLife ◽

10.7554/elife.26991 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 48

Author(s):

Daniela Puzzo ◽

Roberto Piacentini ◽

Mauro Fá ◽

Walter Gulisano ◽

Domenica D Li Puma ◽

...

Keyword(s):

Associative Memory ◽

Memory Impairment ◽

Long Term Potentiation ◽

Neuronal Uptake ◽

Common Mechanism ◽

Tau Oligomers ◽

Term Potentiation ◽

Induced Defects ◽

Oligomeric Forms

The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau.

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