R. Pluta, M. Ułamek, and S. Januszewski. relatively high [3] and an e ect of this incidence is irreversible. Summary
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1 Acta Neurochir (2006) [Suppl] 96: Springer-Verlag 2006 Printed in Austria Micro-blood-brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation in white matter after ischemic brain injury in long-lived rats R. Pluta, M. Ułamek, and S. Januszewski Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland Summary Our study demonstrates that ischemia-reperfusion brain injury induces an increase in blood-brain barrier (BBB) permeability in the periventricular white matter. This chronic insu ciency of BBB may allow entry of neurotoxic fragments of amyloid precursor protein (APP) and other blood components such as platelets into the perineurovascular white matter tissue. These components may have secondary and chronic harmful e ects on the ischemic myelin and axons and can intensify the phagocytic activity of microglial cells. Pathological accumulation of toxic fragments of APP in myelinated axons and oligodendrocytes appears after ischemic BBB injury and seem to be concomitant with, but independent of neuronal injury. It seems that ischemia-reperfusion disturbances may play important roles, both directly and indirectly, in the pathogenesis of white matter lesions. This pathology appears to have distribution similar to that of sporadic Alzheimer s disease. We noted micro-bbb openings in ischemic white matter lesions that probably would act as seeds of future Alzheimer s-type pathology. Keywords: Blood-brain barrier; brain ischemia; horseradish peroxidase; white matter lesions; b-amyloid peptide; leukoaraiosis; Alzheimer s disease. Introduction Brain ischemia-reperfusion injury is a neurodegenerative disease that a ects cognition, behavior, and function. In these types of functional changes, white matter lesions have been implicated in the neuropathogenesis seen in the subcortical and periventricular areas [4, 5, 12, 15]. These white matter lesions are referred to as leukoaraiosis [15]. Leukoaraioses have been found in the brains of patients with ischemic stroke and Alzheimer s disease [14]. The study of brain white matter changes in experimental ischemia has long been neglected because white matter was considered less vulnerable [3]. It is now known that the incidence of ischemic stroke involving white matter is relatively high [3] and an e ect of this incidence is irreversible dysfunction [15]. Recent findings propose an early, silent, cumulative, and significant role for ischemia-reperfusion factors contributing to the development of sporadic Alzheimer s disease [6]. The profile of white matter neuropathology that is observed in brain ischemia probably shares a commonality with the same changes in Alzheimer s disease brain. In this study, we explored the role and impact of ischemia-reperfusion on brain white matter neurodegeneration and its connection with possible development of Alzheimer s disease injury. Because it is not clear whether the blood-brain barrier (BBB) in ischemic white matter lesions is altered in long-lived animals, we investigated BBB insu ciency and staining of di erent fragments of amyloid precursor protein (APP) in the perineurovascular space. In view of the potential late e ects of various extravasated proteins on the development of white matter neurodegenerative changes [13], we discuss the possible influence of chronic ischemic BBB dysfunction on Alzheimer s-type cognitive impairment. We also focus on the question of whether or not the neuropathological mechanism(s) observed in ischemic white matter lesions are the same as those observed in Alzheimer s disease. Materials and methods Using female Wistar rats (n ¼ 5), BBB dysfunction [10], distributions of APP around BBB vessels [5, 8], and platelet pathology [5, 9] were examined in white matter after 10 minutes of brain ischemia [7] then the rats were allowed to survive for 1 year. As controls (n ¼ 3), sham operated rats were sacrificed at the appropriate time. Rat brains were perfusion-fixed for light and electron microscopic analy-
2 268 R. Pluta et al. Fig. 1. Vibratome sections reacted for HRP histochemistry. (A) Extravasated HRP (arrowhead) in subcortical white matter (40). (B) Extravasated HRP (arrowhead) in white matter close to lateral ventricle (40). (C) High magnification of leaking area noted by arrowhead in Fig. 1B (200). (D) Evidence of leakage of HRP in vessel branches/bifurcations in area of lateral ventricle (200) sis [5, 10]. Horseradish peroxidase (HRP) (Type VI, Sigma-Aldrich Co., St. Louis, MO) served as an indicator of BBB changes [5, 10]. HRP was injected into the femoral vein and allowed to circulate for 30 minutes [10]. One hemisphere was cut at mm in the coronal plane with a Vibratome (Vibratome, St. Louis, MO) [5]. For demonstration of HRP, all brain tissue slices were incubated in a solution of 3,3 0 -diaminobenzidine tetra-hcl [10]. After mounting slices on microscope slides, they were examined using light microscopy. Some sections from the second hemisphere were selected for ultrastructural studies [5, 10]. Electron microscopy was performed using a Hitachi H-7000 transmission electron microscope (Hitachi High- Technologies, Krefeld, Germany) [5, 10]. For immunocytochemistry, we used monoclonal antibody (mab) 22C11 against the N- terminal of APP, mab 6E10 and polyclonal antibodies (pab) SP28 against di erent parts of b-amyloid peptide, and pab RAS 57 against the C-terminal of APP [4, 5, 8, 12]. Results Postischemic white matter demonstrated chronic insu ciency of BBB. These micro-bbb lesions predominated in periventricular white matter and were random and spotty (Fig. 1A D). HRP extravasations involved veins, venules, capillaries, and arterioles, and were restricted to branches and bifurcations of these vessels ( Fig. 1D). Frequently we observed damaged endothelial cells and pericytes filled with HRP. The outer walls of the micro-vessels were also labeled with HRP. At the same time, di use deposits of neurotoxic fragments of C-terminals of APP surrounded the BBB vessels, forming perivascular cu s with rarefaction of neighboring tissue and parallel staining of oligodendrocytes ( Fig. 2A C). In this investigation, we noted immunoreactivity for C-terminals of APP and b-amyloid peptide inside vessels predominantly in capillaries. C- terminals of APP and b-amyloid peptide deposits dominated in the paramedian part of the corpus callosum ( Fig. 2A). Perivascular deposits of cytotoxic proteins from APP took the same form as extravasated HRP. Additionally, our study revealed numerous platelet aggregates of varying sizes inside and outside brain veins, venules, microcirculation, and arterioles. Aggregating platelets were in various stages of disintegration. The platelets inside and outside vessels were irregularly shaped and had large numbers of pseudopodia. The endothelial cell surfaces of the leaking microvessels were consistently abnormal, having attached platelets and occasional remnants of platelets with or without contact with endotheium. Examination of vessels demonstrated pseudopodial projections extending from platelets that were inserted into the luminal endothelial
3 Micro-blood-brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation 269 Fig. 2. (A) Perivascular C-terminal of APP-positive material in subcortical white matter and in corpus callosum (arrowheads) (100). (B) High magnification of vessel noted with 2 arrowheads in Fig. 2A. Rarefaction of white matter in vicinity of vessel (400). (C) b-amyloid peptidepositive material surrounding 2 vessels in border between subcortical white matter and corpus callosum. Rarefaction of white matter in vicinity of vessels (400) cell surface. Endothelial microvillus projections were also seen extending toward the luminal platelets. Some vessels were partially or completely plugged by aggregating platelets and their membranous remnants. Endothelial cells demonstrated both functional activation and pathological changes with clear evidence of perivascular edema. Platelet aggregates, like BBB changes and C-terminals of APP deposits, were focal, random, and dispersed. C-terminals of APP deposits and platelet pathology correlated well with BBB insufficiency. Control rat brains showed no HRP leakage, and APP staining and platelet deposition inside and outside vessels. Discussion This study implicated chronic insu ciency of BBB in white matter after a period of ischemia followed by long reperfusion as a secondary event in the pathological changes during ischemic neurodegeneration. The di use distribution of neurotoxic fragments of APP [16] around BBB vessels suggests an uncontrolled passage of these proteins through the endothelial cell body. This was confirmed by intravenous injection of human b-amyloid peptide into ischemic rats [11]. On other hand, di use leakage of HRP and C-terminals of APP through the endothelial cell cytoplasm may indicate chronic endothelial cell damage. Extravasations of cytotoxic parts of APP [16], which was most marked in the paramedian part of the corpus callosum facing the lateral ventricle, may suggest a vulnerability of the BBB vessels in this region, or it may indicate the evacuation of C-terminals of APP fragments through the ependymal cells of the lateral ventricle to cerebrospinal fluid. Our finding of pseudopodial projections in both platelets and endothelial cells directed toward each other provides physical evidence for endothelial cell/platelet adhesion and attachment [9]. This may have an important functional role in transendothelial platelet passage
4 270 R. Pluta et al. and destruction [5, 9]. Chronic micro-bbb lesions [5] and platelets in the perivascular space [5, 9] combined with extravasated neurotoxic fragments of APP [16] may be involved in the gradual maturation of an injurious process in ischemic white matter, which may lead to severe and progressive dementia over a lifetime. Progressive damage of the white matter after ischemia may be caused not only by degeneration of axons and neurons destroyed during ischemic injury, but also by pathological changes in BBB vessels with deposition of neurotoxic fragments of APP. Accumulation of the cytotoxic fragments of APP in ischemic axons as granule-like deposits probably represents inhibition of axoplasmic flow with eventual axotomy and irreversible injury. On the other hand, the presence of blood components outside BBB vessels [2, 5, 9, 11] may have harmful e ects on myelin directly [13] and may enhance the phagocytic activity of microglial cells [1]. The exact mechanism(s) by which the white matter injury occurs in ischemic stroke and Alzheimer s disease is unknown; the trigger can be brain ischemia with secondary chronic BBB dysfunction. This idea is supported by random and di use white matter changes that are related to a BBB injury [14, 15]. We further examined the role of cerebral ischemia injury with an alternative hypothesis proposing that repetitive and silent periods of micro-ischemic-reperfusion may form the basis for development of chronic neurodegenerative disorders such as sporadic Alzheimer s disease [6]. This process may occur by increasing the sensitivity of ischemic neurons and ischemic white matter to b- amyloid peptide formation and aberrant APP processing and/or extravasations of neurotoxic fragments of APP [16] through ischemic BBB from blood [2, 5, 11]. The BBB acts as a doorkeeper of the neurons internal milieu. It is recognized that the BBB protects neuronal cell bodies and axons from injury, not only by stopping toxic substances but also by regulating the optimal extracellular environment required for proper functioning of the neuronal network in the brain. The neuropathology in our study appears to have a similar distribution to that of sporadic Alzheimer s disease [2, 6, 14]. We found chronic micro-bbb openings in ischemic white matter that probably would act as seeds of future Alzheimer s-type pathology. Conclusion Our data indicates that chronic insu ciency of BBB in white matter following ischemia-reperfusion injury is a fundamental event in the maturation of neurodegenerative processes in the neuronal network. Acknowledgments This work was supported in part by funds from European Community, Polish Community of Scientific Research and Medical Research Centre. References 1. D Andrea MR, Cole GM, Ard MD (2004) The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging 25: Mehta PD, Pirttila T (2002) Biological markers of Alzheimer s disease. Drug Dev Res 56: Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27: Pluta R (2000) The role of apolipoprotein E in the deposition of b-amyloid peptide during ischemia-reperfusion brain injury. A model of early Alzheimer s disease. Ann NY Acad Sci 903: Pluta R (2003) Blood-brain barrier dysfunction and amyloid precursor protein accumulation in microvascular compartment following ischemia-reperfusion brain injury with 1-year survival. Acta Neurochir [Suppl] 86: Pluta R (2004) From brain ischemia-reperfusion injury to possible sporadic Alzheimer s disease. Curr Neurovasc Res 1: Pluta R, Lossinsky AS, Mossakowski MJ, Faso L, Wisniewski HM (1991) Reassessment of a new model of complete cerebral ischemia in rats. Method of induction of clinical death, pathophysiology and cerebrovascular pathology. Acta Neuropathol (Berl) 83: Pluta R, Kida E, Lossinsky AS, Golabek AA, Mossakowski MJ, Wisniewski HM (1994) Complete cerebral ischemia with short-term survival in rats induced by cardiac arrest. I. Extracellular accumulation of Alzheimer s b-amyloid protein precursor in the brain. Brain Res 649: Pluta R, Lossinsky AS, Walski M, Wisniewski HM, Mossakowski MJ (1994) Platelet occlusion phenomenon after short- and long-term survival following complete cerebral ischemia in rats produced by cardiac arrest. J Himforsch 35: Pluta R, Lossinsky AS, Wisniewski HM, Mossakowski MJ (1994) Early blood-brain barrier changes in the rat following transient complete cerebral ischemia induced by cardiac arrest. Brain Res 633: Pluta R, Barcikowska M, Januszewski S, Misicka A, Lipkowski AW (1996) Evidence of blood-brain barrier permeability/ leakage for circulating human Alzheimer s b-amyloid-(1 42)- peptide. Neuroreport 7: Pluta R, Barcikowska M, Kida E, Zelman I, Mossakowski MJ (1997) Late extracellular deposits of b-amyloid precursor protein in ischaemic rat brain show di erent immunoreactivity to the N- and C-terminal. Alzheimer Res 3: Silberberg DH, Manning MC, Schreiber AD (1984) Tissue culture demyelination by normal human serum. Ann Neurol 15: Tomimoto H, Akiguchi I, Suenaga T, Nishimura M, Wakita H, Nakamura S, Kimura J (1996) Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer s disease patients. Stroke 27:
5 Micro-blood-brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation Ueno M, Tomimoto H, Akiguchi I, Wakita H, Sakamoto H (2002) Blood-brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab 22: Yokota M, Saido TC, Tani E, Yamaura I, Minami N (1996) Cytotoxic fragment of amyloid precursor protein accumulates in hippocampus after global forebrain ischemia. J Cereb Blood Flow Metab 16: Correspondence: Ryszard Pluta, Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5 Str., Warsaw, Poland. pluta@medres.cmdik.pan.pl
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