Search

Background: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain. Objective: To study the association of polymolphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD. Design: Alzheimer disease traits (β-amyloid load, β-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations. Setting: Specialized centers for memory disorders in Switzerland, Greece, and Italy. Participants: Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies. Results: A polymorphism of CYP46 was associated with increased β-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of β-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CT], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E ∈4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CT, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E ∈4 alone (95% CT, 2.8-6.8; P<.001). Conclusion: CYP46 influences brain β-amyloid load, cerebrospinal fluid levels of β-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD. [ABSTRACT FROM AUTHOR]

Amyloid-beta peptides (Abeta) are major components of amyloid plaques in the Alzheimer's disease (AD) brain and have been proposed as diagnostic markers in cerebrospinal fluid (CSF). Abeta derived from brain may be processed into fragments before emerging in CSF. Therefore, we determined mass profiles of Abeta peptides in CSF of patients with AD and age-matched healthy control subjects (CTR) by using protein biochip technology. Abeta peptides were captured on the chip surfaces (spots) by the specific monoclonal antibody 6E10 and were then analyzed by integrated surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS). We found Abeta species with mean molecular masses at 1,583.3 Da (corresponding to Abeta2-14), 2,068.5 Da (Abeta1-17), 2,166.4 Da (Abeta1-18), 3,676.6 Da (Abeta1-33), 3,789.4 Da (Abeta1-34), 4,076.9 Da (Abeta1-37), 4,134.0 Da (Abeta1-38), 4,233.3 Da (Abeta1-39), 4,332.4 Da (Abeta1-40) and 4,516.8 Da (Abeta1-42) in both AD (n = 24) and CTR (n = 24) subjects. Abeta1-38 appeared to be a major Abeta species in human CSF along with Abeta1-40. Quantitation revealed that CSF levels of Abeta1-38 were significantly decreased in AD as compared to CTR subjects. The CSF profile of Abeta peptides may be used for diagnostic and therapeutic purposes in clinical studies., (Copyright 2004 S. Karger AG, Basel.)

Background: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy., Objective: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD., Methods: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects., Results: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%)., Conclusion: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Background: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain., Objective: To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD., Design: Alzheimer disease traits (beta-amyloid load, beta-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations., Setting: Specialized centers for memory disorders in Switzerland, Greece, and Italy., Participants: Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies., Results: A polymorphism of CYP46 was associated with increased beta-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CI], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E epsilon4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CI, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E epsilon4 alone (95% CI, 2.8-6.8; P<.001)., Conclusion: CYP46 influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.