Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.eelin is an extracellular 420-kDa glycoprotein that binds to the transmembrane receptors apolipoprotein receptor 2 and very-low-density lipoprotein receptor (1, 2), which transduce the Reelin signal through the intracellular adapter disabled-1 (3-5). Reelin signaling triggers a disabled-1-dependent signaling cascade involving several kinases, which ultimately controls proper neuronal migration and positioning during CNS development (for review see ref. 6).The complex pattern of Reelin expression is consistent with evidence that this protein has multiple roles in brain development and adult brain function (7-9). In the adult mammalian brain, Reelin has been proposed to influence synaptogenesis and neural plasticity and to favor memory formation (8)(9)(10)(11)(12). Reelin is also expressed in peripheral tissues, including the liver, and is detected in blood (10, 13). However, whether brain and other tissues contribute to the pool of Reelin in blood remains to be elucidated. In this context, we recently reported the presence of detectable levels of Reelin in adult cerebrospinal fluid (CSF) (14).Furthermore, the involvement of the Reelin signaling pathway in neurodegeneration has also been proposed (1,6,9,(15)(16)(17). First, Reelin binds to apolipoprotein E (ApoE) receptors, and some ApoE gene polymorphisms are considered risk factors for Alzheimer's disease (AD). Moreover, the lack of Reelin is associated with increased phosphorylation of Tau (1, 2, 18), whose hyperphosphorylation leads to intracel...

Studies of the pathogenesis of hepatic encephalopathy are hampered by the lack of a satisfactory animal model. We examined the neurological features of rats after bile duct ligation fed a hyperammonemic diet (BDL؉HD). Six groups were studied: sham, sham pair-fed, hyperammonemic, bile duct ligation (BDL), BDL pair fed, and BDL؉HD. The BDL؉HD rats were made hyperammonemic via an ammonia-containing diet that began 2 weeks after operation. One week later, the animals were sacrificed. BDL؉HD rats displayed an increased level of cerebral ammonia and neuroanatomical characteristics of hepatic encephalopathy (HE), including the presence of type II Alzheimer astrocytes. Both BDL and BDL؉HD rats showed activation of the inflammatory system. BDL؉HD rats showed an increased amount of brain glutamine, a decreased amount of brain myo-inositol, and a significant increase in the level of brain water. In coordination tests, BDL؉HD rats showed severe impairment of motor activity and performance as opposed to BDL rats, whose results seemed only mildly affected. In conclusion, the BDL؉HD rats displayed similar neuroanatomical and neurochemical characteristics to human HE in liver cirrhosis. Brain edema and inflammatory activation can be detected under these circumstances. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). H epatic encephalopathy (HE) is a severe neuropsychiatric complication in both acute and chronic liver failure. Although the pathophysiology of this disorder is incompletely understood, there is agreement on the important role of neurotoxins in its development, especially ammonia. 1 Neuropathologically, HE in chronic liver disease is characterized by astrocytic rather than neuronal changes. 2 Histopathology studies of brain sections from patients with cirrhosis who died in hepatic coma show the presence of changes known as Alzheimer type II astrocytosis. These astrocytes display a specific characteristic of swollen cytoplasm containing a large pale nucleus, with prominent nucleolus and patches of heterochromatin associated with the nuclear envelope. 2 Recently, a new pathophysiological hypothesis has been developed, emphasizing the role of low-grade brain edema in the pathogenesis of HE in chronic liver disease. 3 Following this theoretical model, the presence of a lowgrade astrocyte swelling could have important functional consequences despite the absence of clinically overt increases of intracranial pressure. 3