It seems that the ECM is involved in establishing the developing brain (laminar organization of the cortex/hippocampus, synaptic connections, etc.) to such an extent that it would also have to involved in the neurodegeneration. Could this be a target for drug development?
Perineuronal nets surround mostly the paralbumin producing fast spiking basket interneurons. PNN which forms the extracellular matrix prevent plasticity after critical period. It has been shown that degrading important compartments of PNNs help to enhance plasticity. It can be a target for drug development
I know that in the context of TBI (Traumatic Brain Injury) neurodegeneration this is most certainly a point of concern and is valid therapeutic target. You may already be familiar with this but briefly, after TBI a mechanical depolarization occurs leading to an influx of calcium (among many other subsequent cascades). Up to a point, mitochondria provide a sink for the net calcium influx.
However, subsequent formation of peroxynitirie(PN)-derived radicals and the consequently increased lipid peroxidation (leading to additional free radicals and oxidative damage) disrupt mitochondrial respiration and general homeostasis. Oxidative damage perpetuates the inability of mitochondria to control for the TBI-induced calcium influx and activates calcium-activated proteolytic enzymes, namely calpain and calcineurin. Calpain activation leads to the cytoskeletal degradation and ultimately overall neurodegeneration.
Calpain is also implicated in as a theraputic targer for Azheimer's disease. I've attached two articles. One for TBI context and another for AD context. Hope, that helped. I realize, however, TBI context may not exactly be the neurodegeneration that you were looking into.
Article Calpain as a Therapeutic Target in Traumatic Brain Injury
The second article.
Article Modulation of mitochondrial calcium as a pharmacological tar...
I believe that this may be a tremendously important question, especially among tauopathies (AD included), which feature elements suggestive of a reactivation of developmental functions during neurodegeneration. Tau is involved in neuropathological features (re-expression of cyclins suggesting cell cycle re-entry, the growth of neuropil threads) reminiscent of its developmental functions (axonogenesis, establishment of neuronal polarity). What makes this interesting in the context of the ECM is the strong binding between tau and heparin sulfate proteoglycans, which are ubiquitous in the CNS. We recently published a study describing morphogen-like distribution patterns of secreted tau in our cell-autonomous tau secretion model (Le et. al. 2012, Am J. Neurodegen Dis.). We found that N terminal tau fragments showed flatter tissue distribution gradients than full length tau, which is consistent with modulation via HSPG interactions with the tau MT binding domain.
The CNS extracellular matrix (ECM) undergoes structural and functional changes during development. The mature ECM is a complex structure that contributes to the characteristic pathophysiological changes in the CNS, notably axonal sprouting and regeneration, and glial migration response during neurodegeneration. In addition to present mainstream topics (e.g., hydrolytic enzymes, beta amyloid etc.), I would like to point out less explored topics which may however, and I am surely biased, prove to be of central importance for drug development: Lysyl oxidase-catalyzed cross linking and Hyaluronate binding protein. - Enjoy your research!
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Interesting players in ECM remodelling and neurodegeneration are metalloproteinases (see the review: Yang Y, Hill JW, Rosenberg GA. “Multiple roles of metalloproteinases in neurological disorders.” Prog Mol Biol Transl Sci. 2011;99:241-63. doi: 10.1016/B978-0-12-385504-6.00006-3). In our lab we have retrieved significative alterations in metalloproteinase and their tissue inhibitor in sporadic patients affected by Amyotrophic lateral sclerosis (Bossolasco et al, “Metalloproteinase alterations in the bone marrow of ALS patients”J Mol Med (Berl). 2010 Jun;88(6):553-64. doi: 10.1007/s00109-009-0584-7). They could also be interesting pharmacological targets.
Actually there are plenty reference to report it. Just try to search in Pubmed and you would find whatever you want. Good luck.
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