It is now well established that the extracellular matrix (ECM) and heparan sulfates (HS) are a key regulator of the cellular brain microenvironment. In the MaTTau project, we propose a new strategy to reconstruct the cellular microenvironment in the neurodegenerating brain in the case of tauopathies by rebuilding the ECM scaffold and promoting homeostasis with OTR4132, a HS mimetic which will restore the glycanic ECM, the blood-brain barrier (BBB) and protect the brain cells using the rTg4510 mouse model of tau pathology. Indeed, “tauopathies” include heterogenous neurodegenerative disorders characterized by abnormal deposition of the microtubule-associated protein tau (MAPT) in neurons and, at lower levels, in oligodendrocytes, astrocytes and extracellular space, with symptoms of dementia and parkinsonism. The emerging evidence shows that restoring ECM and HS homeostasis and then the regenerative microenvironment can have drastic consequences on slowing down the progression of the disease, brain speed improvement and recovery. Therefore, HS appeared to be the key elements that promote recovery when ECM niche is lost/altered in injured or degenerating brain tissue. Our preliminary studies highlighted the neurotrophic activity of OTR4132, assessed by neurite outgrowth, and decrease of tau pathology readouts in vitro in a dose-response manner. Additionally, RGTA®-based HS mimetic OTR4132 is capable of significantly protecting the brain against stroke injuries and neurodegeneration leading to BBB disruption, which also induces neurofibrillary tangle-like tauopathy as observed in Alzheimer patients. Recently, we showed the neuroprotective effect of OTR4132 in brain ischemia reperfusion models of stroke in vivo. In addition, by evaluating the regulation of the inflammatory process associated with the fate of the abnormal tau protein and by studying the protein interactions of OTR4132, we will highlight the mechanisms involved in these processes.