The extracellular matrix (ECM) fills the space between cells, providing a meshed network for cells to grow, attach to, and migrate through. Although the ECM is crucial to the healthy function of cells, it is often overlooked in research circles where the common focus is biology within the cell.
Now, a research group based in Yale has established that neurons in the hippocampal region of the brain are able to secrete laminin-5 (an ECM protein), which in turn is vital to the stability and function of neuronal synapses and dendritic spines.
Neuronal synapses and dendritic spines are key to brain function and inter-connectivity between neurons. Damage in these connections – especially in the hippocampus – are implicated in the pathology of Alzheimer’s disease.
Synapses And Spines
The group established that laminin-5 (a specific subunit species of laminin proteins) is necessary to maintain the structure of dendritic spines.
When researchers removed laminin-5 from both in vitro and in vivo experiments it resulted in disruptions to synapse and dendritic spine size, integrity and function.
The results were correlated to behavioural effects in a mouse model, with mice deficient in laminin-5 (laminin-5 knockout mice) performing significantly worse than normal wild type mice.
The test used by the group was a novel object recognition experiment, where mice are familiarised with an object. The learned recognition should allow mice to recognise when a new object is introduced.
With the synaptic disruptions between synapses, it would be expected that the laminin-5 deficient mice would struggle with this task, as exemplified by an inability to recognise new objects.
Researchers also established that laminin-5 binds to a type of cell membrane receptor from the integrin family to elicit an effect on the neuronal connections.
The discovery of the mechanism which laminin-5 acts is important as it allows for the potential production of therapeutics that can target this integrin receptor.
This ties laminin-5 to both neural and vascular diseases and could be applied to better understand and treat diseases of the brain which have a vascular component to their pathology.
The neurovascular benefits of laminin-5 are of potential significance in Alzheimer’s disease, where there is a clear link between both loss of synaptic connections and vascular dysfunction.
Blood vessel dysfunction is thought to contribute to disease progression through a reduced clearance of Alzheimer’s disease related proteins, in particular amyloid beta peptide, which will misfold and aggregate around neuronal synapses, killing brain cells.
Novel therapeutics are a necessity for Alzheimer’s disease and similar neurodegenerative diseases, with a distinct lack of treatments available at present. A drug that targeted the laminin-5 integrin receptor would have the potential to treat both the neural deficits seen in Alzheimer’s disease, but also the neurovascular deficits, through the dual action effect of laminin-5 on neural and vascular cell health.
As most therapeutics to enter clinical trials for Alzheimer’s disease focus on only one aspect of the disease (none of these drugs have made it to the market), there is a strong argument for therapeutic strategies to target more than one pathway in the disease pathogenesis.
The complex and varied mechanisms which lead to the onset and progression of Alzheimer’s disease indicate that a singular target may not be good enough for treatment.
Extracellular Matrix Impact
The intriguing results presented in this study exemplify the importance of the ECM to brain health and the profound affect that is has on cell function and subsequent animal (or human) behaviour.
Further research into the extracellular matrix and its effects on disease and health may lead to more interesting and useful discoveries like those shown here.
Mitchell H. Omar, Meghan Kerrisk Campbell, Xiao Xiao, Qiaonan Zhong, William J. Brunken, Jeffrey H. Miner, Charles A. Greer, Anthony J. Koleske CNS Neurons Deposit Laminin α5 to Stabilize Synapses Cell Reports. 2017 October 31. DOI: http://dx.doi.org/10.1016/j.celrep.2017.10.028
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: hippocampal neuron showing dendritic spines (green), and axons/dendrites (red). Credit: Cheng Fang.