Pericytes in Neurodegeneration

The brain microvasculature is formed of different cell types, where endothelial cells, forming the vessel tube, are encircled by pericytes. Both cell types are ensheathed in a basal lamina, and covered by astrocyte end-feet and neurons, forming altogether the neurovascular unit. Brain pericytes play a pivotal role in angiogenesis, blood-brain barrier (BBB) maintenance and clearance of brain byproducts. Pericytes express numerous markers, such as (i) Regulator for G-protein signaling 5 (RGS5) and Chondroitin sulphate proteoglycan NG2 (NG2), upregulated during vascular remodelling, and (ii) Platelet-derived growth factor receptor beta (PDGFRβ), a specific receptor for PDGF- BB, secreted by endothelial cells for pericyte recruitment on the blood vessels.
The neurovasculature has recently gained attention in neurodegenerative disorders such as Parkinson’s (PD) and Huntington’s (HD) disease, where blood vessel alterations, BBB disruption and cerebral blood flow abnormalities were reported and suggested to contribute to disease onset and progression. In PD and HD, there is a need for neurorestorative therapies, as only symptomatic treatments are currently available in both rodent models of PD and in PD patients. PDGF-BB infusion into the brain lateral ventricle has shown promising results, although the mechanism behind the PDGF-BB-mediated neurorestorative effect remains unclear.
Therefore, this thesis aimed at (i) investigating the pericyte alterations during PD and HD pathology progression, and (ii) examining the pericyte changes upon PDGF-BB treatment in PD. For this, we used a specific transgenic knock-in mouse expressing the green fluorescent protein gene under the Rgs5 promoter, which was subjected to a partial 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Moreover, we also used a transgenic mouse model of PD, overexpressing the human alpha-synuclein (α-syn) gene under the mouse α-syn promoter. To examine pericyte changes in HD, we crossed the R6/2 mouse model of HD with Rgs5 transgenic mice.
In the α-syn transgenic PD mouse model, an increase in vascular density occurs in the striatum at the early stage of the disease, while blood vessel regression is observed later, when behavioural deficits were observed. The vascular regression was also coupled with an increased PDGFRβ+ pericyte number. The latter was also detected in the striatum of the partial 6-OHDA lesion mouse model of PD, together with an increase in the RGS5+ and NG2+ pericyte numbers. Interestingly, PDGF-BB treatment not only induced neurorestoration of the nigrostriatal pathway, associated with behavioural recovery, but also normalized the number of RGS5+ and NG2+ pericytes. Moreover, in vitro, PDGF-BB-stimulated human brain pericytes released several growth factors as well as a greater quantity of microvesicles containing similar growth factors. In HD, vascular changes occurred early during disease progression, with an increase in PDGFRβ+ pericyte number at early stage, when no motor deficits are present, which persisted at later stage of the disease, associated with behavioural impairment, in the R6/2 mouse striatum and the HD post mortem brain. In particular, RGS5+ pericyte number increased solely at earlier disease stage, while NG2+ pericyte numbers were increased only at late stage, in HD.
In summary, this thesis highlights pericyte changes occurring during PD and HD progression, with some pericyte alterations even preceding neuronal cell loss and behavioural impairment. The brain vasculature, and more specifically brain pericytes, may therefore be a potential cell target for future therapies in PD and HD.