Microvascular injury and blood–brain barrier leakage in Alzheimer's disease
Introduction
Impaired cognitive function and short-term memory clinically characterize Alzheimer's disease (AD) [52]. Underlying pathologic features of AD include neuronal and synaptic loss in the cerebral cortex as well as β-amyloid-containing diffuse and neuritic plaques (senile plaques), intraneuronal neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy [14], [25], [39], [52].
While pathologic vascular aberrations are commonly observed in both healthy elderly and AD patients [33], their contribution to the pathogenesis of AD remains largely unstudied. Both vascular risk factors and vascular disease closely correlate with the incidence of AD [10]. Homozygosity of the APOE4 allele on chromosome 19 has been associated with an increased risk of sporadic Alzheimer's disease through mechanisms that remain to be defined [13]. The strong association among vascular pathology, ApoE genotype, and AD dementia suggests that microvascular damage may be a factor in the pathogenesis of AD.
Most human studies of age-related cerebral vascular pathology have focused on atherosclerotic occlusion of the major arteries and arteriolar sclerosis (lipohyalinosis) of the arterioles. Our observation that the solubility properties of agrin are altered in AD, resulting in basement membrane thinning and discontinuity, as well as a redistribution of agrin within neuritic plaques, has led us to hypothesize that blood–brain barrier leakage may be a primary event in the pathogenesis of AD [7], [19], [53].
The exact relationship between cerebral capillaries and senile plaques remains a mystery. In carefully performed ultrastructural analyses, capillaries were consistently observed within senile plaques, suggesting that the latter may result from leaky capillaries [41], [42]. Others, however, have argued that this is largely a chance association and observed no evidence that capillary damage is a prerequisite for senile plaque formation [34].
SPECT and PET scans have documented a preferential decrease in cerebral blood flow to brain areas affected by AD [15], [20], [22], [44], [45]. CT and MRI have shown an increase in small vessel pathology in AD patients [18], [55], [56]. Ironically, despite the widespread recognition of in vivo microvascular dysfunction and significant pathologic alteration in AD patients, the utility of these techniques for demonstrating a defect in BBB integrity has been elusive. It should be noted, however, that most modern imaging techniques have a maximum resolution of approximately 1–10 mm, which may be insufficient to resolve subtle defects in the BBB [28].
The presence of plasma-derived proteins within the perivascular neuropil has been previously shown to be a reliable indicator of early blood–brain barrier compromise in diseases affecting the central nervous system [48], [50], [51]. Prothrombin, a 72 kDa pre-propeptide synthesized in the liver, is best known for its essential role in the coagulation cascade [16], [17]. Circulating prothrombin is largely excluded from the CNS by the blood–brain barrier [38].
In a previous study of the cerebral microvasculature in AD, we reported that prothrombin immunoreactivity in control prefrontal cortex was limited to faint staining within the lumen of vessels and focal staining of cortical neurons [7]. In severe Alzheimer's disease, there was a notable shift in the distribution of prothrombin reaction product. A penumbra of staining became evident within the perivascular neuropil [7]. In the present study we examine the changes in the distribution of prothrombin immunoreactivity that occur at the various Braak stages of Alzheimer's disease severity and correlate these changes with biochemical analyses of prothrombin concentration and APOE genotype.
Section snippets
Human tissues
All brains were obtained postmortem within 1–18 h of death (Table 1). The diagnosis of Alzheimer's disease was made in accordance with accepted National Institute of Aging criteria [61]. AD staging was determined using the criteria of Braak and Braak [9]. APOE genotype in all AD cases was determined by PCR [54]. Control brains were obtained from patients who displayed no pathological evidence of AD or clinical history of neurological disease. All AD patients died as a result of pneumonia,
Results
Patients were divided into three different groups according to their Braak stage of pathologic severity as well as a control group (Table 1).
Discussion
These studies provide evidence that in advanced AD (Braak stage V–VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood–brain barrier may be more common in patients with at least one APOE4 allele. Prothrombin leakage appears to be independent of amyloid angiopathy and may even precede its development. In addition, our data suggest that endothelial cell injury may contribute to plasma protein leakage, although the
Acknowledgments
This work was supported by AG05128, AG09301, NS27601, AG17975, and Glaxo Smith Kline. The authors thank John Ervin and Victoria Kuo-LeBlanc for their technical assistance, and Robin Kiernan for her help in preparing this manuscript.
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