Occludin is overexpressed in Alzheimer's disease and vascular dementia

The tight junctions (TJs) are key players in the control of blood-brain barrier (BBB) properties, the most complex TJs in the vascular system being found in the endothelial cells of brain capillaries. One of the main TJs proteins is occludin, which anchors plasma membranes of neighbour cells and is present in large amounts in the brain endothelia. Previous studies demonstrated that disruption of BBB in various pathological situations associates with changes in occludin expression, and this change could be responsible for malfunction of BBB. Therefore in this study, applying an immunohistochemical approach, we decided to explore the occludin expression in frontal cortex (FC) and basal ganglia in ageing control, Alzheimer's disease (AD), and vascular dementia (VD) brains, as far as all these pathologies associate microangiopathy and disruption of BBB. Strikingly, we found selected neurons, astrocytes and oligodendrocytes expressing occludin, in all cases studied. To estimate the number of occludin-expressing neurons, we applied a stereological approach with random systematic sampling and the unbiased optical fractionator method. We report here a significant increase in ratio of occludin-expressing neurons in FC and basal ganglia regions in both AD and VD as compared to ageing controls. Within the cerebral cortex, occludin was selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings could be important in unravelling new pathogenic pathways in dementia disorders and new functions of occludin and TJs.     

Neuroglia in the inferior olivary nucleus during normal aging and Alzheimer's disease

It is likely that neuronal loss occurs in certain brain regions in Alzheimer's Disease (AD) without any neurofibrillary pathology. In the human principle inferior olivary nucleus (PO), we have shown that neuronal loss is about 34% (Lasn et al. Journal of Alzheimer Disease, 2001; 3: 159-168), but the fate of the neuroglial cells is unknown. Since the unique network of neurons and neuroglial cells and their cohabitation are essential for normal functioning of CNS, we designed a study to estimate the total number of oligodendrocytes and astrocytes in normally aged and AD brains. The study is based on 10 control and 11 AD post-mortem human brains. An unbiased stereological fractionator method was used. We found significant oligodendroglial cell loss (46%) in AD as compared to control brains, while the total number of astrocytes showed a tendency to decrease. It is likely that the ratio of oligodendroglial cells to neurons remains unchanged even in degenerative states, indicating that oligodendroglial cells parallel neuronal loss. Astroglial cells did not increase in total number, but the ratio to neurons was significantly increased due to the neuronal loss. Using a novel unbiased quantitative method, we were able to describe significant oligodendroglial loss in the PO but the pathogenic mechanism behind remains unknown.     

Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease

Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the "Vascular hypothesis", holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration.     

Astrocyte mediated modulation of blood-brain barrier permeability does not correlate with a loss of tight junction proteins from the cellular contacts

In the central nervous system (CNS) complex endothelial tight junctions (TJs) form a restrictive paracellular diffusion barrier, the blood-brain barrier (BBB). Pathogenic changes within the CNS are frequently accompanied by the loss of BBB properties, resulting in brain edema. In order to investigate whether BBB leakiness can be monitored by a loss of TJ proteins from cellular borders, we used an in vitro BBB model where brain endothelial cells in co-culture with astrocytes form a tight permeability barrier for ³H-inulin and ¹⁴C-sucrose. Removal of astrocytes from the co-culture resulted in an increased permeability to small tracers across the brain endothelial cell monolayer and an opening of the TJs to horseradish peroxidase as detected by electron microscopy. Strikingly, opening of the endothelial TJs was not accompanied by any visible change in the molecular composition of endothelial TJs as junctional localization of the TJ-associated proteins claudin-3, claudin-5, occludin, ZO-1 or ZO-2 or the adherens junction-associated proteins -catenin or p120cas did not change. Thus, opening of BBB TJs is not readily accompanied by the complete loss of the junctional localization of TJ proteins.This work is dedicated to the memory of Werner Risau (died 13.12.1998), who initiated this collaboration     

Neuronal localization of the TNFα converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques

The tumor necrosis factor (TNF)‐α converting enzyme (TACE) can cleave the cell‐surface ectodomain of the amyloid‐β precursor protein (APP), thus decreasing the generation of amyloid‐β (Aβ) by cultured non‐neuronal cells. While the amyloidogenic processing of APP in neurons is linked to the pathogenesis of Alzheimer's disease (AD), the expression of TACE in neurons has not yet been examined. Thus, we assessed TACE expression in a series of neuronal and non‐neuronal cell types by Western blots. We found that TACE was present in neurons and was only faintly detectable in lysates of astrocytes, oligodendrocytes, and microglial cells. Immunohistochemical analysis was used to determine the cellular localization of TACE in the human brain, and its expression was detected in distinct neuronal populations, including pyramidal neurons of the cerebral cortex and granular cell layer neurons in the hippocampus. Very low levels of TACE were seen in the cerebellum, with Purkinje cells at the granular‐molecular boundary staining faintly. Because TACE was localized predominantly in areas of the brain that are affected by amyloid plaques in AD, we examined its expression in a series of AD brains. We found that AD and control brains showed similar levels of TACE staining, as well as similar patterns of TACE expression. By double labeling for Aβ plaques and TACE, we found that TACE‐positive neurons often colocalized with amyloid plaques in AD brains. These observations support a neuronal role for TACE and suggest a mechanism for its involvement in AD pathogenesis as an antagonist of Aβ formation. © 2001 John Wiley & Sons, Inc. J Neurobiol 49: 40–46, 2001     

基于单细胞转录组的基因富集方法分析星形胶质细胞与阿尔茨海默病的关系*

目的:通过生物信息学方法分析阿尔茨海默病(Alzheimer disease, AD)中与星形胶质细胞相关的糖代谢通路,为揭示AD患者的星形胶质细胞在大脑中的糖代谢过程提供理论基础。方法:首先根据细胞特异性表达基因将AD患者和健康人脑组织单细胞转录组学测序结果进行降维分析,再根据星形胶质细胞不同亚型的基因表达特征进行细胞分群,对星形胶质细胞差异表达基因进行基因注释(Gene Ontology. GO)、信号通路分析(Kyoto Encyclopedia of Genes and Genomes, KEGG)以及基因集富集分析(Gene Set Enrichment Analysis, GSEA),采用转录调控网络分析与AD的星形胶质细胞相关的转录辅助因子。结果:所有细胞降维分析结果显示AD患者脑内星形胶质细胞和兴奋性神经元数量显著减少;星形胶质细胞降维分析结果显示其可以被进一步分为6个亚群,其中在AD患者中减少的星形胶质细胞主要为RASGEF1B⁺SLC26A3⁺亚群和NRGN⁺CALM1⁺亚群;GO分析结果显示AD患者与健康对照星形胶质细胞差异表达基因主要与轴突发生、神经元的迁移、胶质细胞分化、体内锌离子稳态、突触传递的正调控、血管运输有关。KEGG结果显示,上述差异基因主要与PI3K-Akt信号通路、AMPK信号通路、钙信号通路有关。GSEA分析结果显示,AD患者差异基因在糖酵解/糖异生通路中得到富集,其中丙酮酸激酶PKM、PFKL、ACSS1、乳酸脱氢酶LDHB在AD患者星形胶质细胞中下调。转录调控网络分析结果显示,星形胶质细胞中差异表达转录辅助因子有5个,其中PKM、SOX2、SOX9在AD患者星形胶质细胞中下调。SREBF1和BCL6在AD患者星形胶质细胞中上调。结论:AD患者脑内兴奋性神经元和星形胶质细胞数量降低,以及星形胶质细胞糖酵解相关基因下调。结合星形胶质细胞作为神经元的主要乳酸供应细胞,其数量减少和糖酵解能力减低提示星形胶质细胞供能不足可能是AD发生的机制之一。     

Neuronal localization of the TNFalpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques

The tumor necrosis factor (TNF)-alpha converting enzyme (TACE) can cleave the cell-surface ectodomain of the amyloid-beta precursor protein (APP), thus decreasing the generation of amyloid-beta (Abeta) by cultured non-neuronal cells. While the amyloidogenic processing of APP in neurons is linked to the pathogenesis of Alzheimer's disease (AD), the expression of TACE in neurons has not yet been examined. Thus, we assessed TACE expression in a series of neuronal and non-neuronal cell types by Western blots. We found that TACE was present in neurons and was only faintly detectable in lysates of astrocytes, oligodendrocytes, and microglial cells. Immunohistochemical analysis was used to determine the cellular localization of TACE in the human brain, and its expression was detected in distinct neuronal populations, including pyramidal neurons of the cerebral cortex and granular cell layer neurons in the hippocampus. Very low levels of TACE were seen in the cerebellum, with Purkinje cells at the granular-molecular boundary staining faintly. Because TACE was localized predominantly in areas of the brain that are affected by amyloid plaques in AD, we examined its expression in a series of AD brains. We found that AD and control brains showed similar levels of TACE staining, as well as similar patterns of TACE expression. By double labeling for Abeta plaques and TACE, we found that TACE-positive neurons often colocalized with amyloid plaques in AD brains. These observations support a neuronal role for TACE and suggest a mechanism for its involvement in AD pathogenesis as an antagonist of Abeta formation.     

Selective expression of eGFP in mouse perivascular astrocytes by modification of the Mlc1 gene using T2A‐based ribosome skipping

Perivascular astrocyte end feet closely juxtapose cerebral blood vessels to regulate important developmental and physiological processes including endothelial cell proliferation and sprouting as well as the formation of the blood‐brain barrier (BBB). The mechanisms underlying these events remain largely unknown due to a lack of experimental models for identifying perivascular astrocytes and distinguishing these cell types from other astroglial populations. Megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1) is a transmembrane protein that is expressed in perivascular astrocyte end feet where it controls BBB development and homeostasis. On the basis of this knowledge, we used T2A peptide‐skipping strategies to engineer a knock‐in mouse model in which the endogenous Mlc1 gene drives expression of enhanced green fluorescent protein (eGFP), without impacting expression of Mlc1 protein. Analysis of fetal, neonatal and adult Mlc1‐eGFP knock‐in mice revealed a dynamic spatiotemporal expression pattern of eGFP in glial cells, including nestin‐expressing neuroepithelial cells during development and glial fibrillary acidic protein (GFAP)‐expressing perivascular astrocytes in the postnatal brain. EGFP was not expressed in neurons, microglia, oligodendroglia, or cerebral vascular cells. Analysis of angiogenesis in the neonatal retina also revealed enriched Mlc1‐driven eGFP expression in perivascular astrocytes that contact sprouting blood vessels and regulate blood‐retinal barrier permeability. A cortical injury model revealed that Mlc1‐eGFP expression is progressively induced in reactive astrocytes that form a glial scar. Hence, Mlc1‐eGFP knock‐in mice are a new and powerful tool to identify perivascular astrocytes in the brain and retina and characterize how these cell types regulate cerebral blood vessel functions in health and disease.     

Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models

ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.     

Engraftment,migration and differentiation of neural stem cells in the rat spinal cord following contusion injury

Background aimsSpinal cord injury is a devastating injury that impacts drastically on the victim's quality of life. Stem cells have been proposed as a therapeutic strategy. Neural stem (NS) cells have been harvested from embryonic mouse forebrain and cultured as adherent cells. These NS cells express markers of neurogenic radial glia.MethodsMouse NS cells expressing green fluorescent protein (GFP) were transplanted into immunosupressed rat spinal cords following moderate contusion injury at T9. Animals were left for 2 and 6 weeks then spinal cords were fixed, cryosectioned and analyzed. Stereologic methods were used to estimate the volume and cellular environment of the lesions. Engraftment, migration and differentiation of NS cells were also examined.ResultsNS cells integrated well into host tissue and appeared to migrate toward the lesion site. They expressed markers of neurons, astrocytes and oligodendrocytes at 2 weeks post-transplantation and markers of neurons and astrocytes at the 6-week time-point. NS cells appeared to have a similar morphologic phenotype to radial glia, in particular at the pial surface.ConclusionsAlthough no functional recovery was observed using the Basso Beattie Bresnahan (BBB) locomotor rating scale, NS cells are a potential cellular therapy for treatment of injured spinal cord. They may be used as delivery vehicles for therapeutic proteins because they show an ability to migrate toward the site of a lesion. They may also be used to replace lost or damaged neurons and oligodendrocytes.     

Carbonic Anhydrase, 5''-Nucleotidase, and 2'',3''-Cyclic Nucleotide-3''-Phosphodiesterase Activities in Oligodendrocytes, Astrocytes, and Neurons Isolated from the Brains of Developing Rats

The activities of three myelin-associated enzymes, carbonic anhydrase, 5'-nucleotidase, and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP), were measured in oligodendrocytes, neurons, and astrocytes isolated from the brain of rats 10, 20, 60, and 120 days old. The carbonic anhydrase specific activity in oligodendrocytes was three- to fivefold higher than that in brain homogenates at each age, and, at all the ages, low activities of this enzyme were measured in neurons and astrocytes. The oligodendrocytes and astrocytes from the brains of rats at all ages had higher activities of the membrane-bound enzyme 5'-nucleotidase than was observed in neurons. In oligodendrocytes from 10- and 20-day-old rats, the 5'-nucleotidase activity was two-to threefold the activity in the homogenates (i.e., relative specific activity = 2.0-3.0), and the relative specific activity of this enzyme in the oligodendrocytes declined to less than 1.0 at the later ages, concomitant with the accumulation of 5'-nucleotidase in myelin. The CNP activity was always higher in oligodendrocytes than in neurons, but not appreciably different from that in astrocytes from 20 days of age onward. The relative specific activity of CNP was highest in the oligodendrocytes from 10-day-old rats but was lower, at all ages, than we had observed in bovine oligodendrocytes. These enzyme activities in oligodendroglia are quite different in amount and developmental pattern from those reported previously for myelin.     

Expression of Neuronal CXCL10 Induced by Rabies Virus Infection Initiates Infiltration of Inflammatory Cells,Production of Chemokines and Cytokines,and Enhancement of Blood-Brain Barrier Permeability

It has been shown that enhancement of blood-brain barrier (BBB) permeability is modulated by the expression of chemokines/cytokines and reduction of tight junction (TJ) proteins in the brains of mice infected with rabies virus (RABV). Since CXCL10 was found to be the most highly expressed chemokine, its temporal and spatial expression were determined in the present study. The expression of the chemokine CXCL10 was initially detected in neurons as early as 3 days postinfection (p.i.) in the brains of RABV-infected mice, after which it was detected in microglia (6 days p.i.) and astrocytes (9 days p.i.). Neutralization of CXCL10 by treatment with anti-CXCL10 antibodies reduced gamma interferon (IFN-γ) production and Th17 cell infiltration, as well as restoring TJ protein expression and BBB integrity. Together, these data suggest that it is the neuronal CXCL10 that initiates the cascade that leads to the activation of microglia/astrocytes, infiltration of inflammatory cells, expression of chemokines/cytokines, reduction of TJ protein expression, and enhancement of the BBB permeability.     

The Distribution and Biochemical Properties of a Cdc2-Related Kinase, KKIALRE, in Normal and Alzheimer Brains

Abstract: The biochemical properties and distribution of a Cdc2-related kinase, KKIALRE, were studied in brain tissues and cultured cells with antibodies to a subregion of KKIALRE protein deduced from cDNA. In adult human brain, the KKIALRE-immunoreactive protein consisted of four or five isoforms having a molecular size of 40–52 kDa, whereas in fetal brain, there was one protein of ∼48 kDa. Cultured astrocytes, neuroblastoma cells, and mouse brains contained the fetal form of KKIALRE protein. KKIALRE-immunoreactive proteins were capable of phosphorylating histone and synthetic peptides with the X-Ser-Pro-X motif, indicating that these proteins belong to the proline-directed Ser/Thr protein kinase family. The KKIALRE immunoreactivity was detected primarily in fibrous astrocytes in white matter and perivascular and subpial spaces, as well as in Bergmann glia in the cerebellum. In fetal brains radial glia were weakly immunoreactive. Reactive astrocytes were more intensely labeled than other glia. Neurons in normal brains and brains with Alzheimer's disease (AD) displayed no KKIALRE immunoreactivity. KKIALRE immunoreactivity was similar in neurons with and without neurofibrillary tangles. The results indicate that in CNS, the KKIALRE protein is mainly a glial protein that is up-regulated in gliosis and that it probably plays no role in the hyperphosphorylation of τ in AD brains.     

The role of amino acid transporters in GSH synthesis in the blood-brain barrier and central nervous system

Glutathione (GSH) plays a critical role in protecting cells from oxidative stress and xenobiotics, as well as maintaining the thiol redox state, most notably in the central nervous system (CNS). GSH concentration and synthesis are highly regulated within the CNS and are limited by availability of the sulfhydryl amino acid (AA) l-cys, which is mainly transported from the blood, through the blood-brain barrier (BBB), and into neurons. Several antiporter transport systems (e.g., x(c)(-), x(-)(AG), and L) with clearly different luminal and abluminal distribution, Na(+), and pH dependency have been described in brain endothelial cells (BEC) of the BBB, as well as in neurons, astrocytes, microglia and oligodendrocytes from different brain structures. The purpose of this review is to summarize information regarding the different AA transport systems for l-cys and its oxidized form l-cys(2) in the CNS, such as expression and activity in blood-brain barrier endothelial cells, astrocytes and neurons and environmental factors that modulate transport kinetics.     

Vascular Cognitive Disorder. A Biological and Clinical Overview

Although vascular dementia (VaD) represents the second most common cause of dementia after Alzheimer’s disease (AD) in the elderly, and is referred as the “silent epidemic of the twenty-first century”, there is still a controversy on terminology, classification and diagnostic criteria of VaD. The diagnosis of VaD resides in clinical criteria determining a cognitive impairment, the presence of cerebrovascular disease and, only in the case of post-stroke dementia or multi-infarct dementia, a temporal relationship between these. The search for a reliable biochemical tests helping in the diagnosis of VaD is so far not available. Several vascular risk factors have a role in the development of VaD and their identification and treatment are among the major aspects of management of VaD. A new line of research in this field is the study of genetic factors underlying vascular cognitive impairment which are: (1) genes predisposing to cerebrovascular disease, and (2) genes that influence brain tissue responses to cerebrovascular lesions. Evidence in favour of a coexistence of vascular and degenerative components in the pathogenesis of dementia in an elderly population comes from neuropathological and epidemiological studies. There is now a great debate whether VaD and AD are more than common coexisting unrelated pathologies and, instead, represent different results of synergistic pathological mechanisms. Preventive approaches aiming at reducing incident VaD by targeting patients at risk of cerebrovascular disease (primary prevention), or acting on patients after a stroke (secondary prevention) to prevent stroke recurrence and the progression of brain changes associated with cognitive impairment are mandatory therapeutic strategies.     

Astrocytes support incomplete differentiation of an oligodendrocyte precursor cell.

Glial fibrillary acidic protein-positive astrocytes, but not neurons or fibroblasts, support the differentiation of an oligodendroglial precursor cell expressing O4 antigen and vimentin into an O4 antigen-positive, but vimentin-negative oligodendrocyte. Further maturation into galactocerebroside (O1)-positive oligodendrocytes is, however, not achieved under the culture conditions used, neither in the presence of astrocytes nor neurons.     

p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease

The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.     

Molecular composition of tight and adherens junctions in the rat olfactory epithelium and fila

Tight and adherens junctions (TJs, AJs) between neurons, epithelial and glial cells provide barrier and adhesion properties in the olfactory epithelium (OE), and subserve functions such as compartmentalization and axon growth in the fila olfactoria (FO). Immunofluorescence and immunoelectronmicroscopy were combined in sections of rat OE and FO to document the cellular and subcellular localization of TJ proteins occludin(Occl), claudins(Cl) 1-5 and zonula occludens(ZO) proteins 1-3, and of AJ proteins N-cadherin(cad), E-cad, and alpha-, beta- and p120-catenin(cat). With the exception of Cl2, all TJ proteins were colocalized in OE junctions. Differences in relative immunolabeling intensities were noted between neuronal and epithelial TJs. In the FO, Cl5-reactivity was localized in olfactory ensheathing cell (OEC) junctions, Cl1-reactivity in the FO periphery, with differential colocalization with ZOs. Supporting cells formed N-cad-immunoreactive (ir) AJs with olfactory sensory neurons, E-cad-ir junctions with microvillar and gland duct cells, and both N-cad and E-cad-ir junctions in homotypic contacts. Alpha, beta- and p120-cat were localized in all AJs of the OE. AJs were scarce in the globose basal cell layer. Immature and mature neurons formed numerous contacts. In the FO, AJs were documented between OECs, between OECs and axons, and between axons. Most AJs colocalized N-cad with catenins, occasionally E-cad-ir AJs were found in the FO periphery. Characteristics of molecular composition suggest differential properties of TJs formed by neuronal, epithelial and glial cells in the OE and FO. The presence and molecular composition of AJs are consistent with a role of AJ proteins in neuroplastic processes in the peripheral olfactory pathway.     

Cerebrospinal fluid markers in differential diagnosis of Alzheimer's disease and vascular dementia

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common causes of dementia in old people. They remain difficult to differentiate in practice because of lack of sensitivity and specificity of current clinical diagnostic criteria. Recent molecular and cellular advancements indicate that the use of cerebrospinal fluid markers may improve early detection and differential diagnosis of AD. Our objective in this study was to determine diagnostic accuracy of three cerebrospinal (CSF) markers: total tau protein (t-tau), tau protein phosphorylated on threonine 181 (p-tau181) and tau protein phosphorylated on serine 199 (p-tau199). Using commercially available ELISA kits concentrations of t-tau, p-tau181 and p-tau199 were analyzed in 12 patients with probable AD, 9 patients with VaD and 12 NC subjects. The median levels of all three markers were significantly higher in AD group versus VaD and NC groups. However, when the sensitivity levels were set to 85% or higher, only t-tau and p-tau199 satisfied consensus recommendations (specificity more than 75%) when differentiating AD from VaD. In conclusion, our preliminary data on a small group of selected subjects suggest that the CSF t-tau and p-tau199 levels are useful markers for differentiating AD from VaD.