Aggregation of the microtubule-associated protein tau, associated with several neurodegenerative disorders, including AD and frontotemporal dementia is thought to occur via prion-like network propagation, whereby protein

aggregates released into the extracellular space enter specific neighbouring cells and trigger further fibrillogenesis [330]. A recent study elucidated the mechanism by which this occurs, in which tau fibrils enter cells by HSPG-dependent macropinocytosis to seed further aggregation, which in vivo could be blocked by use of a heparin mimetic. In addition, this mechanism was also reported to mediate aggregation of α-synuclein, found both in AD and in neurodegenerative disorders associated with Lewy body aggregates such as Lewy body dementia and Parkinson’s disease [331]. Targeting Small molecule library concentration of HSPGs therefore represents a promising therapeutic strategy in neurodegenerative diseases in which pathological aggregates propagate. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease. In most sclerotic lesions, OPCs are present but do not differentiate into mature myelinating oligodendrocytes, where increasing failure to remyelinate progresses with disease chronicity [332]. In MS there is altered expression of ECM proteins and these are implicated in ongoing pathology. Both diffuse ECM and basement membrane are affected. For example,

in acute, active periods of demyelination there is a decrease in parenchymal tenascin and CSPG lectican levels. In inactive lesions tenascin levels return to baseline and the lecticans versican, aggrecan and neurocan Sirolimus molecular weight are chronically upregulated.

PTK6 This is thought to result from macrophage phagocytosis in the active lesion and persistent reactive gliosis in the chronic lesion respectively [333–335]. The ECM is also known to be involved in the regulation of OPC migration, proliferation and differentiation into myelinating oligodendrocytes [336]. Furthermore, accumulation of high-molecular-weight hyaluronan has been shown to inhibit OPC maturation and remyelination of chronic lesions in the experimental autoimmune encephalomyelitis (EAE) model of MS pathology [337]. Basement membrane components are also known to regulate multiple processes in myelination as well as immune cell infiltration to lesions. For example, laminin-2 is implicated in OPC survival and differentiation via integrin, contactin and dystroglycan receptor interactions [338–341], downstream potentiation of growth signalling [342] and also specific regulation of actin-cytoskeleton mediated OPC extension of myelinating processes [343] and its expression is upregulated in MS lesions [344]. In contrast, increased expression of fibronectin in MS, which is both localized to basement membrane and also expressed parenchymally in the active lesion [345], impairs remyelination [346].