Human α-synuclein overexpression in a mouse model of Parkinson’s disease leads to vascular pathology, blood brain barrier leakage and pericyte activation

Abstract

The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood–brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.

High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease

“…In PD both, post-mortem data and cerebrospinal fluid analyses have shown changes in small blood vessels and markers of blood–brain barrier (BBB) leakage as part of the progressive brain pathology [ 14 – 17 ] . The findings in post-mortem studies are supported by preclinical animal studies in toxin-induced PD models [ 18 , 19 ] and recently also in a progressive α-syn PD model [ 20 ], pointing to a temporal dynamic of vascular changes in PD with an initial compensatory angiogenesis and vascular rarefication at later stages of the disease [ 20 ].…”

“…Microvascular alterations are a common denominator of several neurodegenerative disorders [ 44 ] and have been described as part of the pathology in PD [ 18 , 20 , 45 ]. Similarly, DMT2 leads to vascular alterations also in the brain [ 25 ], and the effect of DMT2 on the brain microvasculature in PD models, however, is not known.…”

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

“…Moreover, the question arises as to whether toxic proteins and hemostatic factors also trigger microvascular, BBB and CBF alterations contributing to neurodegenerative disorders in other brain amyloidosis, such as Parkinson’s disease. Interestingly, a recent study revealed that overexpression of human α-synuclein, the toxic counterpart to Aβ in Parkinson’s disease [ 23 ], led to brain vascular pathology, BBB dysfunction with fibrinogen leakage, and pathological activation of pericytes in a mouse model of this disease [ 125 ]. Possibly, further investigations on the role of brain vasculature [ 126 ] and hemostatic factors, e.g., thrombin, fibrin(ogen) [ 78 ], contributing to neurodegeneration in other amyloidosis, such as Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, might lead to the hypothesis that DOACs, such as dabigatran, could be helpful also in treating vascular dysfunction in these neurodegenerative diseases.…”

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

“…In rat brain ECs and pericytes co-culture, monomeric α-synuclein induced the release of inflammatory cytokines from pericytes and increased the permeability of brain ECs [ 144 ]. A mouse model overexpressing human α-synuclein showed vascular pathology and BBB disruption, and these changes were accompanied by pericyte activation [ 145 ].…”