Jean-Marie Serot

Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease.

Serum apolipoprotein (apo) AI concentration was studied in 98 Alzheimers disease (AD) patients (77.56+/-8.83 years) and 59 healthy, elderly controls (75.37+/-5.27 years). ApoAI levels were significantly lower (p<10(-7)) in AD patients. An apoAI cutoff value of 1.50 g/L, could distinguish between the two groups with a sensitivity of 71% and a specificity of 69%. ApoAI levels were highly correlated with mini-mental state (MMSE) scores of patients (p<0.0001). These relationships remained significant after adjustment for multiple testing. Our findings raise the question of the potential implication of apoAI in the etiopathology of AD and bring serum apoAI concentration to the fore as an important biochemical marker.

Increased protein glycation in cerebrospinal fluid of Alzheimer’s disease

Accumulation of advanced glycation end products occurs in the brain with ageing and was proposed to be involved in pathogenesis of Alzheimers disease. We studied changes in the level of an early glycation product, an Amadori product, in cerebrospinal fluid (CSF) in ageing and in late-onset Alzheimers disease. The work was carried out on 99 consecutive patients. The concentration of Amadori product in CSF correlated with CSF glucose concentration but was not changed with age (n = 70). In contrast, level of CSF Amadori product was 1.7-fold higher in Alzheimers disease patients (n = 29) as compared with non-demented age-matched control group (n = 20; P < 0.0005), although CSF glucose concentration was similar in both groups (4.1 +/- 1.3 vs. 3.8 +/- 0.6 mmol/liter, resp.). An increased accumulation of Amadori products was found in all major proteins of CSF of Alzheimers disease including albumin, apolipoprotein E and transthyretin. We propose that the increased early glycation of CSF proteins in the Alzheimers patients may stimulate the formation and the consequent deposition of advanced glycation end products as well as oxidative stress in the brain.

CHOROID PLEXUS, AGEING OF THE BRAIN, AND ALZHEIMER'S DISEASE

: Choroid plexus tissues are intraventricular structures composed of villi covered by a single layer of ciliated, cuboid epithelium. The plexuses secrete cerebrospinal fluid (CSF), synthesize numerous molecules, carry nutrients from the blood to CSF, reabsorb brain metabolism by-products and participate in brain immunosurveillance. During ageing, atrophy of epithelium occurs along with thickening of basement membranes. Enzymatic activities of epithelial cells decrease significantly. CSF secretion decreases as much as 50%. These modifications are concurrent with subnormal brain activity. In Alzheimers disease, epithelial atrophy, thickening of basement membrane and stroma fibrosis are even more prominent. Ig and C1q deposition along the basement membrane can be frequently detected, suggesting immunological processes. Synthesis, secretory, and transportation functions are significantly altered resulting in decreased CSF turnover, reduced beta-amyloid clearance, and increased glycation phenomena as well as oxidative stress. Such modifications may favour fibrillary transformation of beta-amyloid protein and tau protein polymerisation.

Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry

We measured the levels of two β‐amyloid (Aβ)‐sequestering proteins, apolipoprotein (Apo) E and transthyretin (TTR), in ventricular human cerebrospinal fluid (CSF) of Alzheimers disease (AD) patients and controls in relation to brain histological findings. We also studied actin levels in CSF as a marker of the biochemical role of these two proteins in the cytoskeleton. We show that TTR levels in CSF were significantly decreased in AD patients compared to controls and negatively correlated with the senile plaque (SP) abundance. Moreover, actin levels were positively linked to TTR levels and increased in CSF samples of patients homozygous for the ApoE ϵ4‐allele. We propose that TTR and ApoE4 may have competition in the aggregation of Aβ and its deposition in the SP of AD brain. The relationships between ApoE, TTR and actin could suggest a metabolic implication of ApoE genetics and TTR levels in cytoskeletal biochemistry which may be relevant to the pathogenesis of AD.

Morphological alterations of the choroid plexus in late-onset Alzheimer's disease.

Abstract Anomalies of the cerebrospinal fluid flow rate and composition that have been reported in patients suffering from Alzheimer’s disease (AD) could be related to alterations of the choroid plexuses (CD). Here we report a photonic and electron morphometric study in which we compared the height of CP epithelial cells and the thickness of their basement membrane on post-mortem samples from AD patients, age-matched controls and two new-borns. Ageing appeared associated with epithelial atrophy and basement membrane thickening, but these features were significantly accentuated in AD. These data suggest that a dramatic alteration of the secretion and filtration could be involved in the multiparametric pathogenesis of late-onset AD.

CSF-folate levels are decreased in late-onset AD patients.

Summary. Folates are involved in the cerebral metabolism of cobalamine, methionine, L-tyrosine and acetylcholine. Remarkably CSF-folate levels are 3 to 4 times higher than blood-folate levels. To reach the brain, folates are actively transported by choroid plexus (CP) as well as vitamins B6, B12, C and E. Epithelial atrophy having been reported in aging and in Alzheimers disease (AD), we measured the CSF folate-levels of 126 patients, including 30 AD consecutive patients to evaluate whether CP functions of folate-transport were impaired. CSF-folate concentrations did not vary with age (10.47 ± 1.93 ng/ml between 20 and 60 years; 9.96 ± 2.01 ng/ml in elderly control patients older than 60 years of age, p > 0.05) while late-onset AD patients had significantly lower CSF-folate levels (8.26 ± 1.82 ng/ml, p < 0.001). These data support a specific alteration of CP transport function in AD patients.

Ultrastructural and immunohistological evidence for dendritic-like cells within human choroid plexus epithelium.

ULTRASONIC examination of human choroid plexus (CP) disclosed the presence of a possibly new type of CP cells displaying many of the features of dendritic cells and apparently expressing HLA Class II antigens. These cells bear long processes, devoid of tight junctions, inserted between CP epithelial cells, and have close contacts with CP basement membrane. They could, therefore, play a key role in immunosurveillance in the central nervous system.

Monocyte-derived IL-10-secreting dendritic cells in choroid plexus epithelium

Choroid plexuses form an interface between peripheral blood and cerebrospinal fluid. Dendritic-like cells have been reported in a few studies of choroid plexuses in man. Here we used electron microscopy and immunophenotyping to precise the morphologic features and phenotype of these cells. Examination of 10 human choroid plexuses evidenced intra-epithelial dendritic cells with a clear cytoplasm, reniform nucleus and long expansions. These cells express MHC Class II, CD11b, CD14, CD32, CD68 and IL-10, but not CD40, CD80 or CD86, suggesting an immunosuppressive role for these dendritic cells. Their sentinel position could make them participate to the immunological silence of the brain.

Choroid plexus and ageing in rats: a morphometric and ultrastructural study

Choroid plexuses (CP) are intraventricular structures involved in the production of cerebrospinal fluid (CSF) and in the synthesis and transport of numerous CSF components. Age‐related modifications of the CP structure are still ill defined. We performed an ultrastructural and morphometric study of ageing CP in nine Sprague–Dawley rats 6, 18 and 30 months of age. Epithelial cells of CP villi were cubic in shape at 6 months, more dome‐like at 18 months, and significantly flattened at 30 months of age. Epithelial basement membranes were thin and regular at 6 months, significantly thicker at 18 months and thicker and irregular at 30 months. Intravillous stroma increased nonhomogeneously with age. The ageing of CP in rats is characterized morphologically by epithelial atrophy, irregular fibrosis of the stroma and a thickening of epithelial basement membranes. These modifications suggest an alteration of secretory and filtrating functions in ageing CP.

CSF homocysteine, CSF folates and choroid plexus

Selley et al. [9] recently reported an increase of homocysteine and (E)-4-hydroxy-2-nonenal (HNE) levels associated with a decrease of folate levels in plasma and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients. These results and their interpretation should be considered in our opinion in the light of the functions of the blood–brain barrier, particularly at the level of choroid plexuses (CPs). CSF is not formed by a simple passive process of ultrafiltration. About 90% of CSF is actively secreted by CP, the remaining 10% coming from brain interstitial fluid drainage [10]. Folate and vitamin B12 do not diffuse from blood to CSF, but are actively transported in CP [16]. Usually transporters are saturated at half-level, in case of shortage, a recruitement can occur to prevent variations of CSF levels [16]. Folate CSF levels are two of three times (14–18 ng/ml) folate blood levels (3–12 ng/ml) [7,13]. In exceptional cases of alteration of choroid plexus transporter, folate CSF levels are very low while serum levels remain normal [17]. In the reported study by Selley, CSF folate levels in controls are remarkably lower than serum levels, which is in opposition to what is classically reported in the literature [7,13]; this discrepancy could explain the absence of a significant correlation between the increase of homocysteine CSF levels and the decrease of CSF folate in AD patients. CSF amino acid levels are only 40% of plasma levels, being actively transported to CSF through an active mechanism at CP level [5]. Four amino acid transporters have been described, two for large and small amino acids and two for cationic and anionic amino acids [11].