Striatal Blood–Brain Barrier Permeability in Parkinson'S Disease

Abstract

In vivo studies have shown that blood-brain barrier (BBB) dysfunction is involved in the course of Parkinson's disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde transsynaptic hypothesis of PD spread. Keywords: α-synuclein; blood-brain barrier; Parkinson's disease; striatum INTRODUCTION Parkinson's disease (PD) is characterized by aggregation of filamentous or oligomerized α-synuclein and degeneration of specific neuronal regions. According to the dual-hit hypothesis of PD pathogenesis, a microbial or toxic pathogen within the gut lumen and the olfactory mucosa represents the pathogenic agent, with subsequent prion-like spread of pathology, first to the dorsal motor nucleus of the vagus and central olfactory areas, respectively, then to higher centers. The connectional anatomy linking the dorsal motor nucleus and olfactory bulb with higher centers such as the substantia nigra is unproven.We have previously proposed that disease could be spread hematogenously. 1 This is conceivable within the paradigm of retrograde (axon terminal to soma) Lewy pathology spread. 2,3 Almost all regions affected in Braak stage 1 have axon terminals outside the blood-brain barrier (BBB). That same BBB, however, protects the higher-order regions, whose axon terminals reside within the central nervous system, from blood-borne substances. Cell-to-cell spread is a potential mechanism to circumvent this protection but the connectional neuroanatomy is not consistent with the temporal order of Lewy pathology development as it is currently understood.Nigrostriatal dopaminergic neuronal cell bodies develop significant Lewy pathology, but recent studies strongly suggest that α-synuclein aggregation in these cells begins at presynaptic axon terminal in the striatum and spreads retrogradely to nigral

Interleukin-4 Contributes to Degeneration of Dopamine Neurons in the Lipopolysaccharide-treated Substantia Nigra in vivo

“…Astrocytes are well known to maintain the BBB integrity [23], that has shown to be disrupted in patients with PD [33]. BBB protects the brain from potential neurotoxic molecules in circulation via tightly regulating ion balance, nutrient transport, the entry of plasma components and blood cells [23].…”

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…Post-mortem analysis of brain tissue from patients with PD revealed perivascular deposits of fibrinogen or fibrin 165 , IgG 166 and haemosiderin 165,167 in the striatum, which is indicative of BBB breakdown. Fibrin(ogen) deposits around capillaries were also found in brain tissue from patients with HD 60 .…”

“…Extravasation of red blood cells has been found in AD 146 , PD 165 and ALS 62 . Infiltration by peripheral macrophages has also been shown in AD 149,172 and in HIV encephalitis 150 .…”

“…In humans, extracellular vesicles containing α-synuclein have been found in the CSF and blood, suggesting bidirectional transport of this protein between the blood and CSF 237,238 . As red blood cells are a source of α-synuclein-containing extracellular vesicles 237 , and extravasation of red blood cells into the striatum has been detected in patients with PD 165,166 , extravasated red blood cells might contribute to the development of α-synucleinopathy in humans. Since levels of α-synuclein are two orders of magnitude higher in the circulation than in the CNS 238 , α-synuclein transport across the BBB might be implicated in the pathogenesis of PD, and could be a novel therapeutic target.…”

Commentary: “Age-Associated Physiological and Pathological Changes at the Blood-Brain Barrier: A Review”

“…As in Alzheimer's disease and multiple sclerosis, MMPs seem to have implications in Parkinson's disease and are associated with the neurodegeneration of dopaminergic neurons. Concerning the role of active transporters and tight junctions it is concluded that there is much controversy in the literature on the role of the BBB in Parkinson's disease [21,22].…”