amyloid-beta-peptides and Nervous-System-Diseases

Alzheimer's disease (AD) is a major cause of dementia in the elderly. Although early-onset (familial) AD is attributed to gene mutations, the cause for late-onset (sporadic) AD, which accounts for 95% of AD cases, is unknown. In this study, we show that exposure of 6-week-old amyloid beta precursor protein (APP)/presenilin (PS1) overexpressing mice, a well-established animal model of AD, and nontransgenic littermates to a cyclic O3 exposure protocol, which mimics environmental exposure episodes, accelerated learning/memory function loss in male APP/PS1 mice but not in female APP/PS1 mice or nontransgenic littermates. Female APP/PS1 mice had higher brain levels of amyloid beta peptide (Aβ42) and Aβ40, compared with male APP/PS1 mice; O3 exposure, however, had no significant effect on brain Aβ load in either male or female mice. Our results further show that male APP/PS1 mice had lower levels of antioxidants (glutathione and ascorbate) and experienced augmented induction of NADPH oxidases, lipid peroxidation, and neuronal apoptosis upon O3 exposure, compared with female APP/PS1 mice. No significant effect of O3 on any of these parameters was detected in nontransgenic littermates. In vitro studies further show that 4-hydroxynonenal, a lipid peroxidation product which was increased in the plasma and cortex/hippocampus of O3-exposed male APP/PS1 mice, induced neuroblastoma cell apoptosis. Together, the results suggest that O3 exposure per se may not cause AD but can synergize with genetic risk factors to accelerate the pathophysiology of AD in genetically predisposed populations. The results also suggest that males may be more sensitive to O3-induced neuropathophysiology than females due to lower levels of antioxidants.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Brain Chemistry; Female; Lipid Peroxidation; Male; Memory Disorders; Mice; NADPH Oxidases; Nervous System Diseases; Neurons; Ozone; Peptide Fragments; Presenilins; Sex Characteristics

This article presents new information regarding the complement/level of S100 family members expressed in the brain and reviews the contribution of brain S100 family members to nervous system function and disease. A total of ten S100 family members are reported in the literature to be expressed in brain -S100A1, S100A2, S100A4, S100A5, S100A6, S100A10, S100A11, S100A13, S100B, and S100Z. Quantitative Northern blot analysis detected no S100A3, S100A8, S100A9 or S100A14 mRNA in mouse brain suggesting that these family members are not expressed in the brain. In addition, there was a 100-fold range in the mRNA levels for the six family members that were detected in mouse brain: S100A1/S100B levels were 5-fold higher than S100A6/S100A10 levels and 100-fold higher than S100A4/S100A13 levels. Five of these six family members (S1100A1, S100A6, S100A10, S100A13, and S100B) exhibited age-dependent increases in expression in adult mice that ranged from 5- to 20-fold. Although previous studies on S100 function in the nervous system have focused on S100B, other family members (S100A1, S100A3, S100A4, S100A5) have been implicated in neurological diseases. Like S100B, intra- and inter-cellular forms of these family members have been linked to cell growth, cell differentiation, and apoptotic pathways. Studies presented here demonstrate that ablation of S100A1 expression in PC12 cells results in increased resistance to Abeta peptide induced cell death, stabilization of intracellular [Ca2+] homeostasis, and reduced amyloid precursor protein expression. Altogether, these results confirm that S100-mediated signal transduction pathways play an important role in nervous system function/disease and implicate S100A1 in the neuronal cell dysfunction/death that occurs in Alzheimer's disease.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Brain Chemistry; Calcium; Cell Differentiation; Cell Line; Cell Proliferation; Gene Expression Regulation; Homeostasis; Mice; Mice, Inbred C57BL; Nervous System Diseases; Nervous System Physiological Phenomena; Neurons; Peptide Fragments; S100 Proteins; Signal Transduction

Cannabinoid receptor agonists including anandamide and noladin either have recently been suggested to exhibit neuroprotective properties. The amyloid-beta (Abeta) peptide is thought to be responsible for the neurodegenerative changes associated with Alzheimer's disease pathology. This study characterizes the effects of anandamide and noladin ether on the neurotoxicity of Abeta in differentiated human teratocarcinoma cell line, Ntera 2/cl-D1 neurons. Anandamide and noladin ether, at nanomolar concentrations, showed concentration dependent inhibition of Abeta toxicity. A CB(1) cannabinoid receptor antagonist, AM251, prevented the protective effects of anandamide and noladin ether. The mitogen activated protein kinase (MAPK) pathway inhibitor PD98059 also prevented the protective effects of cannabinoids and corticotrophin-releasing hormone. These results suggest that activation of the MAPK pathway by either cannabinoids or corticotrophin-releasing hormone could be used to prevent Abeta peptide induced neurodegeneration.

Topics: Amyloid beta-Peptides; Arachidonic Acids; Cannabinoids; Corticotropin-Releasing Hormone; Endocannabinoids; Enzyme Inhibitors; Flavonoids; Glycerides; Humans; Mitogen-Activated Protein Kinases; Nervous System Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Oxidation-Reduction; Peptide Fragments; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug

Cerebrospinal fluid samples from a total of 157 subjects consisting of 55 patients with sporadic Alzheimer's disease (AD), 34 normal controls, 23 patients with non-AD dementia, and 45 with other neurological diseases were examined by ELISA of tau, A beta 1-40, and A beta 1-42(43). The AD group had a significantly higher level of tau than the normal control group (P < 0.001), and the diagnostic sensitivity was 31% and specificity was 94%. CSF A beta 1-40 levels did not show any significant differences. Although the level of A beta 1-42(43) was decreased significantly in the AD group compared to the control group (P < 0.005), the overlap of A beta 1-42(43) levels among all groups meant that none of the AD samples exceeded the cut-off value, the mean 2SD of normal control subjects. Reduction of A beta 1-42(43) levels in AD resulted in a significant increase in the ratio of A beta 1-40 to A beta 1-42(43) (A beta ratio) as an improved marker. The diagnostic sensitivity and specificity of A beta ratio were 51% and 82% respectively. The three indexes, using the tau level and A beta ratio (tau or A beta ratio, deviation score and tau x A beta ratio), showed better sensitivity (58%, 67%, 69%) and specificity (82%, 86%, 88%) than previously reported methods. Combination assay for CSF tau, A beta 1-40 and A beta 1-42(43) in CSF is a biological marker of AD and may be useful to biochemically monitor subjects under treatment.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Female; Humans; Male; Middle Aged; Nervous System Diseases; Peptide Fragments; Reference Values; tau Proteins

To test whether the concentrations of amyloid-beta (A beta) 40, A beta 42, apolipoprotein E (apoE) and transthyretin in the CSF of normal individuals, are linked to three factors which modulate the risk of Alzheimer's disease (AD): chronological age, gender, and the presence of the apoE4 allele.. Proteins were measured by enzyme-linked immunosorbent assays except for transthyretin, which was assayed by radial immunodiffusion. The apoE phenotype was determined by isoelectric focusing. While the CSF levels of A beta 42, apoE, and transthyretin are reported to be reduced in AD, we found no relationship between age, gene, or apoE phenotype and the level of any of these proteins in the CSF of nondemented individuals. The concentration of A beta 40 was not modulated by gender or apoE phenotype, but did decline significantly with age.. These results indicate that the changes observed in the CSF of AD patients are specific to the disease itself rather than the known risk factors.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Apolipoproteins E; Enzyme-Linked Immunosorbent Assay; Female; Genotype; Humans; Male; Middle Aged; Nervous System Diseases; Peptide Fragments; Prealbumin; Protein Isoforms; Sex Characteristics