Vasculopathy in Alzheimer's disease (AD) may represent an important pathogenetic factor of this disorder. In the present study, microvasculature was studied by immunohistochemistry using a monoclonal antibody against a vascular heparan sulfate proteoglycan. Vascular changes were consistently observed in AD and included decrease in vascular density, presence of atrophic and coiling vessels, and glomerular loop formations. The laminar and regional distribution of these vascular alterations was correlated with the presence of neurofibrillary tangles. However, vascular changes may also follow neuronal loss. Vascular density may be related to a decrease in brain metabolism. Furthermore, one of the main features of AD is the presence of amyloid deposits within brain parenchyma and blood vessel walls. It is not yet clear whether amyloid components are derived from the blood or the central nervous system. Because AD is clearly heterogeneous, based on clinical and genetic data, evidence for either a brain or peripheral origin is discussed. Microvasculature was also analyzed in other neurodegenerative disorders devoid of amyloid deposits including amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam and Pick's disease. In conclusion, if vasculopathy in neurodegenerative disorders is not directly involved in pathogenesis, it may act synergistically with other pathogenetic mechanisms including genetic and environmental factors. This aspect of pathology is particularly interesting in view of its accessibility to therapeutic interventions.

PMID: 9329677, UI: 97470260

Ann Neurol 1997 Sep;42(3):356-359

Pathological tau proteins in postencephalitic parkinsonism: comparison with Alzheimer's disease and other neurodegenerative disorders.

Buee-Scherrer V, Buee L, Leveugle B, Perl DP, Vermersch P, Hof PR, Delacourte A

Immunohistochemical and biochemical analyses of hyperphosphorylated tau proteins, the major component of neurofibrillary tangles, were performed in different brain regions from patients presenting with postencephalitic parkinsonism. Neurofibrillary tangles were found in hippocampus, neocortical areas (mostly in supragranular layers), and several subcortical structures. By immunoblotting, a tau protein triplet similar to the one seen in Alzheimer's disease was observed. This biochemical approach allows for the definition of postencephalitic parkinsonism from certain neurodegenerative disorders such as progressive supranuclear palsy and corticobasal degeneration.

PMID: 9307257, UI: 97450816

Neurosci Lett 1997 Oct 10;235(1-2):53-56

Glial reaction in the hippocampal formation is highly correlated with aging in human brain.

David JP, Ghozali F, Fallet-Bianco C, Wattez A, Delaine S, Boniface B, Di Menza C, Delacourte A

Service de Gerontologie Clinique, Hopital Emile Roux, Limeil Brevannes, France.

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified by immunoblotting in different brain areas from 33 non-demented patients with a Mini Mental State Examination score above 26 and aged from 12 to 98 years. An increase of GFAP with age was first found in the hippocampus and then in the entorhinal cortex. In both regions, GFAP amounts were correlated with age (r = 0.768). In the isocortex, the increase of GFAP as a function of age was also significant (r = 0.672), but less than for the hippocampal region. GFAP levels increased dramatically after the age of 65 years, and more especially in the hippocampal formation. This glial reaction was observed in aged controls that do not show cognitive impairment and the neuropathological hallmarks of Alzheimer's disease.

PMID: 9389594, UI: 98049462

DELACOURTE A, SERGEANT N, ROBITAILLE Y, BUEE-SCHERRER V, BUEE L, DAVID JP, BUSSIERE T, VERMERSCH P, HOF PR, GAUVREAU D, WATTEZ A.

Pathological Tau proteins are biochemical markers that differentiate several types of neurofibrillary degeneration.

in Alzheimer s disease: Biology, diagnosis and Therapeutics. Edited by K. Iqbal, B. Winblad, T. Nishimura, M. Takeda and H. Wisniewski. 1997

Int Rev Cytol 1997;171:167-224

Normal and pathological Tau proteins as factors for microtubule assembly.

Delacourte A, Buee L

Tau proteins are microtubule-associated proteins. They regulate the dynamics of the microtubule network, especially involved in the axonal transport and neuronal plasticity. Tau proteins belong to a family of developmentally regulated isoforms generated by alternative splicing and phosphorylation. This generates several Tau variants that interact with tubulin and other proteins. Therefore, Tau proteins are influenced by many physiological regulations. Tau proteins are also powerful markers of the neuronal physiological state. Their degree of phosphorylation is a good marker of cell integrity. It is heavily disturbed in numerous neurodegenerative disorders, leading to a collapse of the microtubule network and the presence of intraneuronal lesions resulting from Tau aggregation. However, different biochemical and immunological patterns of pathological Tau proteins found among neurodegenerative disorders are useful markers for the understanding of the role of Tau protein isoforms and the diagnosis of these pathological conditions.

Publication Types:

Review
Review, tutorial

PMID: 9066128, UI: 97218704

Neurobiol Dis 1997;4(5):356-364

ApoE synthesis in human neuroblastoma cells.

Dupont-Wallois L, Soulie C, Sergeant N, Wavrant-de Wrieze N, Chartier-Harlin MC, Delacourte A, Caillet-Boudin ML

INSERM U422, Lille, France.

Apolipoprotein E (apoE) is associated with the two hallmarks of Alzheimer's disease: A beta deposits and neurofibrillary tangles. ApoE synthesis was detected in astrocytes by in situ hybridization but was not detected in neurons. Nevertheless, different studies on apoE immunoreactivity reported the presence of apoE in neurons of Alzheimer, control, and necrosis pontisubicular brains. In this study, we addressed the question of potential synthesis of apoE in neurons and its possible involvement in or in response to pathological conditions. To this purpose, we have studied human neuronal cell lines (SY 5Y and Kelly cells) originating from neuroblastoma. Using monoclonal and polyclonal antibodies, a 32-kDa band was detected in SY 5Y and Kelly cells, before and after NGF differentiation. Two-dimensional gel electrophoresis analysis showed a typical profile of apoE spots resolved to the exact isoelectric points. By reverse transcription-polymerase chain reaction experiments, we demonstrated the presence of apoE mRNA in these cell lines. SY 5Y cells synthesized the apoE3 variant, whereas Kelly cells expressed both apoE3 and apoE4 isoforms, corroborating the two-dimensional gel results. These results suggested that apoE synthesis could occur in human neuronal cell lines under certain conditions.

PMID: 9440124, UI: 98103298

Hum Mol Genet 1997 Nov;6(12):2151-2154

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease.

Lambert JC, Perez-Tur J, Dupire MJ, Galasko D, Mann D, Amouyel P, Hardy J, Delacourte A, Chartier-Harlin MC

The APOE straightepsilon4 allele is a strong genetic susceptibility factor for Alzheimer's disease. Interaction with other biological factors may modulate the effect of the apoE isoforms. However, previous work suggested that other genetic variability within the APOE locus, influencing the effect of the straightepsilon4 allele, may exist. Such variability could modify the expression of the APOE gene and, in particular, the level of expression of APOE alleles could be an important determinant of disease pathogenesis. To test this hypothesis we examined the levels of expression of APOE in heterozygotes with AD and in controls, using a new method of semi-quantitation. We report that relative straightepsilon4 mRNA expression is increased in AD compared with controls and suggest that genetic variability in the neural expression of APOE contributes to disease risk.

PMID: 9328480, UI: 97472468

FEBS Lett 1997 Aug 4;412(3):578-582

Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases.

Sergeant N, David JP, Lefranc D, Vermersch P, Wattez A, Delacourte A

Tau proteins aggregate into different neuronal inclusions in several neurodegenerative disorders. In Alzheimer's disease (AD), hyperphosphorylated Tau from paired helical filaments (PHF) of neurofibrillary tangles, named PHF-Tau, have an electrophoretic profile with four main bands (Tau 55, 64, 69, 74 kDa). In Pick's disease, phosphorylated Tau from Pick bodies are made of two major components (Tau 55, 64 kDa) and a minor 69 kDa. Here we show, using specific antibodies against translated exon 2, 3 or 10 of Tau isoforms, that the set of Tau isoforms engaged in the most insoluble part of PHF in AD is made of Tau isoforms with exon 10 while they are lacking in phosphorylated Tau from Pick's disease. Our results suggest that specific sets of Tau isoforms distinguish between typical neuronal inclusions.

PMID: 9276470, UI: 97420485

J Neurochem 1997 Aug;69(2):834-844

Two-dimensional characterization of paired helical filament-tau from Alzheimer's disease: demonstration of an additional 74-kDa component and age-related biochemical modifications.

Sergeant N, David JP, Goedert M, Jakes R, Vermersch P, Buee L, Lefranc D, Wattez A, Delacourte A

PHF-tau proteins are the major components of the paired helical filament (PHF) from Alzheimer's disease (AD) neurofibrillary lesions. They differ both qualitatively and quantitatively in their degree of phosphorylation when compared with native tau proteins. However, little is known about the extent and heterogeneity of phosphorylated sites or the isoform composition and the isoelectric variants of PHF-tau. Therefore, we have characterized PHF-tau proteins from cortical brain tissue homogenates of 13 AD patients using two-dimensional gel electrophoresis. Whatever the topographical origin of brain tissue homogenates, PHF-tau proteins shared the same two-dimensional gel electrophoresis profile made of a tau triplet of 55, 64, and 69 kDa. A 74-kDa hyperphosphorylated tau component was detected particularly in the youngest and most severely affected AD patients. This additional component of hyperphosphorylated tau was shown to correspond to the longest brain tau isoform. Furthermore, the isoelectric points of PHF-tau from older AD patients were significantly more basic, indicating a lower degree of phosphorylation. These results show that the severity of neurofibrillary degeneration of AD is modulated by age.

PMID: 9231745, UI: 97375428
.

J Neurol Neurosurg Psychiatry 1997 Aug;63(2):240-246

Neurofibrillary tangles in Gerstmann-Straussler-Scheinker syndrome with the A117V prion gene mutation.

Tranchant C, Sergeant N, Wattez A, Mohr M, Warter JM, Delacourte A

One patient of a French family with Gerstmann-Straussler-Scheinker syndrome with the mutation in codon 117 of the prion protein (PrP) gene displayed unexpected neuritic degeneration around PrP plaques and numerous diffuse neurofibrillary tangles, whereas other members did not. The tau profile in this patient's brain was analysed and compared with one from another member of the Gerstmann-Straussler-Scheinker family as well as with the Alzheimer's tau profile. A panel of well characterised antibodies against both normal tau protein and paired helical filaments-tau protein was used on immunoblots of brain proteins resolved by mono and two dimensional gels. The tau profile in the patient with Gerstmann-Straussler-Scheinker syndrome without neurofibrillary tangles was normal. The tau profile from the patient with Gerstmann-Straussler-Scheinker syndrome and neurofibrillary tangles was characterised by a hyperaggregation state of tau protein. This case illustrates the phenotypic heterogeneity of the GSS117 mutation not only from one family to another, but also between members of the same family. In this family, the presence of neurofibrillary tangles is still unexplained, but could be correlated with either the protracted duration of the disease or the old age of the patient.

PMID: 9285466, UI: 97429828

Neurosci Lett 1997 May 9;227(1):68-70

Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease.

Wavrant-DeVrieze F, Perez-Tur J, Lambert JC, Frigard B, Pasquier F, Delacourte A, Amouyel P, Hardy J, Chartier-Harlin MC

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people. It usually occurs after 65 years old (late-onset AD). The epsilon4 allele of apolipoprotein E (APOE) gene is a risk factor which contributes about 50% of the genetic risk for this form of the disease. The low density lipoprotein receptor-related protein (LRP) is a major receptor for APOE which is found in the senile plaques of AD brains. This makes it a good candidate gene for the disease. There is a polymorphism in the region upstream of the LRP gene that has been associated with AD in an American population. We examined this polymorphism by restriction fragment length polymorphism analysis in a French population with sporadic late-onset AD. In the previous report, a significant increase of the 87 bp allele was found in the AD cases; however, in our population, we observed a significant decrease with this same allele of the LRP gene. The possible reasons for this discrepancy, linkage disequilibrium or statistical anomaly, are discussed.

PMID: 9178861, UI: 97322207