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Involvement of the Extracellular Matrix in Age-Related Memory Loss in Mice


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Posted 22 July 2014 - 10:26 PM


All of the myriad conditions of degenerative aging stem from comparatively simple roots: a small number of different types of cellular and molecular damage that accumulate over the decades. From there secondary forms of dysfunction spin off into spirals of cause and effect, becoming ever more complex and challenging to interpret at each new turn. It is just the same as rust in a complex metal framework: a simple root cause, but thousands of ways in which the rust can progress to cause the structure to finally collapse.

Treating the consequences of aging has been difficult for the medical research community because they have traditionally started their investigations at the final and most complicated end point, which is to say full-blown age-related disease. From there researchers try to work backwards towards progressively earlier causes. The first points at which they find ways to intervene are the closest proximate causes, which tend to be complex dysregulations of metabolism or cell state. Treatments involve the use of drugs to produce alterations in protein levels or epigenetic changes which in turn change the operation of cells or metabolism - but since everything in cellular biology influences everything else this is hard to get right, and it is also hard to produce benefits without significant side-effects. Also, since this is a matter of targeting proximate causes rather than root causes, the root cause of the problem continues chewing away underneath it all, making any solution temporary and fragile at best.

This is the present state of medicine. In the future, we would like to see a growth in targeting of root causes in aging and age-related disease, as exemplified by the SENS research program that I'm sure you're all at least passingly familiar with by now. A change of this nature in research and development will produce a sweeping improvement in the quality and capabilities of clinical medicine. This is very much a work in progress, however, and still in the earliest stages. The overwhelming majority of medical research continues to focus on end states and proximate causes rather than root causes, and is consequently the hard path to limited benefits.

Occasionally there are moments of luck in the present process, however, where it turns out that a pocket of comparative simplicity in the progression of degeneration from root cause to end state extends a fair way along the chain of consequences. This recently published research suggests that this might be the case for age-related memory loss in mammals. This is an aspect of cognitive decline that I would not have guessed had any simple points of intervention. The nature of the changes involved is also surprising, as it lies outside cells, not inside:

Rigid connections: Molecular basis of age-related memory loss explained

Brain cells undergo chemical and structural changes, when information is written into our memory or recalled afterwards. Particularly, the number and the strength of connections between nerve cells, the so-called synapses, changes. To investigate why learning becomes more difficult even during healthy ageing, the scientists looked at the molecular composition of brain connections in healthy mice of 20 to 100 weeks of age. This corresponds to a period from puberty until retirement in humans. "Amazingly, there was only one group of four proteins of the so-called extracellular matrix which increased strongly with age. The rest stayed more or less the same."

The extracellular matrix is a mesh right at the connections between brain cells. A healthy amount of these proteins ensures a balance between stability and flexibility of synapses and is vital for learning and memory. "An increase of these proteins with age makes the connections between brain cells more rigid which lowers their ability to adapt to new situations. Learning gets difficult, memory slows down."

Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wildtype mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90 and 100 weeks of age.

Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time. This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission.

Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance at old age.

Note that the paper is open access, and the full PDF version is available.


View the full article at FightAging




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