·        Reducing levels of a molecule in perineural nets — cartilage-like brain structures that encase neurons — simulated brain aging in young mice.
·        Restoring levels of this molecule, chondroitin 6-sulphates (C6S), with gene therapy and a drug candidate in aged animals rescued the memory deficits.

The brain is like a 3D roadway where electrochemical information gets shuttled to different regions across nerve highways and streets for us to experience life. Recent work has shown that structures encase some of these routes made of brain cells (neurons) called perineuronal nets. This tunnel-like matrix seals nerve connections and is implicated in the formation and maintenance of memory and the brain’s ability to reorganize itself by forming new neural connections throughout life (neuroplasticity).

New research published in Molecular Psychiatry out of the University of Cambridge shows that manipulating specific components of perineural nets restores neuroplasticity and alleviates memory deficits in aged mice. When Sujeong Yang and her colleagues impeded the generation of a subset of molecules that make up perineuronal nets, the brains of young mice aged rapidly and presented with memory problems. Restoring the levels of these molecules, called chondroitin 6-sulphates, in aged animals, rescued the memory deficits, suggesting a strategy to improve age-related memory impairment.

Professor James Fawcett from the John van Geest Centre for Brain Repair at the University of Cambridge said, “What is exciting about this is that although our study was only in mice, the same mechanism should operate in humans – the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age.”

Perineuronal nets manage brain connections

Perineuronal nets are condensed matrix structures surrounding the cell body (soma) and signal receiving branches (dendrites) of some classes of neurons. A significant subset of neurons are involved in the control of developmental and adult neuroplasticity.

A menagerie of molecules make up perineuronal nets, but their ability to control neuroplasticity depends on the modulation of chemical chains of sugars typically found in cartilage called chondroitin sulphate glycosaminoglycan chains (CS-GAGs). The functions of CS-GAGs can be modulated by patterns of modifications, in particular a process called sulphation — the addition of sulfate to a molecule.

In the central nervous system, two types of chondroitin sulphate (CS) dominate: chondroitin 6-sulphates (C6S) and chondroitin 4-sulphates (C4S). While C6S is permissive to axon growth and plasticity, C4S is inhibitory to neuron growth. The types of CSs change with age, with a late decline in C6S and increased levels of C4S.

For the formation of new neuron connections (synapses) onto other neurons, neuronal processes must penetrate the perineural nets. With levels tipping from C6S to C4S, these cartilage-like structures become more inhibitory with age, and synapse generation underlying the formation of new memories may therefore be partially blocked.

Researchers rescue memory loss in aged mice by perineuronal net attenuation

For these reasons, Yang and colleagues looked into whether the changing perineural net sulphation may be a contributor to age-related memory impairment, and, if so, whether this could be altered. Specifically, they tested if age-related alterations in the types of CSs may make perineural nets more inhibitory, leading to memory loss linked with diminished inhibitory synapse formation onto neurons.

To test this, the University of Cambridge researchers changed the sulphation pattern of perineural nets in young and aged animals and measured memory performance, using memory tests that very aged animals can achieve. Their results show that aged mice develop memory impairment in an assortment of memory tasks concurrent with a decline in the permissive C6S in perineural nets.

Yang and colleagues were then able to induce changes in memory by manipulating the C6S levels in the brain. On the one hand, lowered C6S led to premature memory loss. On the other, enhancing C6S levels prevented age-related memory impairment and restored memory in established age-related memory impairment.

For example, the University of Cambridge researchers injected a virus that produced the enzyme responsible for generating CS6. Upon doing so, they restored levels of short-term neuroplasticity in the central nervous system, which usually declines with aging.

(Yang et al., 2021 | Molecular Psychiatry) Restoration of C6S restores memory in aged mice. (Left, B) Age-mediated memory loss in mice and memory restoration by injection of a virus carrying an enzyme that restores C6S levels (AAV1-Chst3). (Right, C) In genetically modified mice with persistent levels of chst3 (tg), age-mediated memory loss was absent.

Also, Yang and colleagues tested if they could restore the memory impairment in aged mice by injecting a compound called chondroitinase ABC (ChABC), which modifies the CS composition. The results of these experiments echoed that of the viral injection experiments. 

(Yang et al., 2021 | Molecular Psychiatry) Chondroitinase ABC treatment restores memory and neuron network integrity. (Left) Injection of chondroitinase ABC (ChABC), which restores C6S levels, rescued age-related memory deficit. (Right) Integrity of the neuron network — parvalbumin (PV)+ neurons — after ChABC treatment.

“We saw remarkable results when we treated the aging mice with this treatment,” said Dr. Jessica Kwok from the School of Biomedical Sciences at the University of Leeds. “The memory and ability to learn were restored to levels they would not have seen since they were much younger.”

Putting memory loss reversal into action

The changing properties of perineural nets with age are therefore a factor in age-related memory impairment. Targeting sulphation in perineural nets could be an effective means of treating and preventing age-related memory impairment. This study demonstrates that treatments targeting perineural nets can ameliorate memory deficits associated with aging. The approach taken by Professor Fawcett’s team using viral vectors to deliver the treatment is increasingly being used to treat human neurological conditions.

What’s more, the team has already identified a chABC as a potential drug that inhibits the formation of perineural nets. Interestingly, in animal models of Alzheimer’s disease, ChABC has also alleviated the neurodegeneration-related memory loss. We will have to wait to see which of these two approaches wins out in the race to treat memory loss and neurodegenerative diseases like Alzheimer’s.