Sirtuins in Alzheimer's Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics.

Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer's disease (AD), contributing to AD pathogenesis. There is an association between the genotype (rs10410544) (50.

African-American TOMM40'523-APOE haplotypes are admixture of West African and Caucasian alleles.

Background: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of Outer Mitochondria Membrane) and APOE depends on accurate TOMM40'523-APOE haplotypes.

Methods: We have compared the APOE and TOMM40'523 phased haplotype frequencies of a 9.

My story: the discovery and mapping to chromosome 21 of the Alzheimer amyloid gene.

When I decided to clone the amyloid gene I did not know that there were some twenty groups around the research world that desperately tried to do the same. If I knew that I would have never started the project. I was so ignorant about the disease that I did not know how to spell the name Alzheimer.

Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques, cerebrovascular amyloid deposits, intracellular neurofibrillary tangles, and neuronal loss. Amyloid deposits are composed of insoluble fibers of a 39-43 amino acid peptide named the amyloid beta-protein (A beta). Neuropathological and genetic studies provide strong evidence of a key role for A beta amyloidosis in the pathogenesis of AD.

Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults.

Background: Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on beta-amyloid (Abeta). Hyperinsulinemia induces inflammation and is a risk factor for Alzheimer disease. Thus, insulin abnormalities may contribute to Alzheimer disease pathophysiology through effects on the inflammatory network.

Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin variants.

Most transthyretin (TTR) mutations lead to TTR amyloid depositions in patients with familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy. However, though an amyloidogenic protein itself, TTR inhibits aggregation of Alzheimer's amyloid beta protein (A beta) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear.

Somatic symptoms in women 11 years after the Chornobyl accident: prevalence and risk factors.

Exposure to the Chornobyl nuclear power plant explosion resulted in widespread, persistent somatic complaints, but little is known about the nature and risk factors for these conditions. This study compares the health reports of 300 women evacuated to Kyiv from the contamination zone around the plant and 300 controls with a child in the same homeroom as the evacuees in 1997. The interview addressed somatic concerns, risk factors for poor health, and Chornobyl-related stress.

Stress and well-being in mothers of young children 11 years after the Chornobyl nuclear power plant accident.

Background: This paper examines the association between exposure to the Chornobyl nuclear power plant explosion and the psychological and physical well-being of mothers with young children. The study also examines whether exposure to Chornobyl increased the vulnerability of mothers to subsequent economic and social stress, and thus represents a unique test of the stress-vulnerability model in a non-Western setting.

Method: The sample consisted of mothers evacuated from the contamination zone surrounding the plant (evacuees) and mothers who had never lived in a radiation-contaminated area (controls).

Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death.

Ubiquitin-B+1 (UBB+1) is a mutant ubiquitin that accumulates in the neurones of patients with Alzheimer's disease (AD). Here we report on the biochemical and functional differences between ubiquitin and UBB+1 and the effect of the mutant protein on neuronal cells. UBB+1 lacks the capacity to ubiquitinate, and although it is ubiquitinated itself, UBB+1 is not degraded by the ubiquitin-proteasomal system and is quite stable in neuronal cells.

Cdc2 phosphorylation of nucleolin demarcates mitotic stages and Alzheimer's disease pathology.

Nucleolin is a major multifunctional nuclear phosphoprotein that is phosphorylated by Cdc2 kinase in mitosis and that participates in a number of cellular processes. The monoclonal antibody TG-3 generated against neurofibrillary tangles (NFT) found in Alzheimer's disease (AD) is highly specific for mitotic cells in culture. We here demonstrate that phosphorylation of nucleolin by Cdc2 kinase generates the TG-3 epitope.

Ukrainian application of the Children's Somatization Inventory: psychometric properties and associations with internalizing symptoms.

This paper examines the psychometric properties of the Children's Somatization Inventory (CSI) in 600 10-12-year old children in Kyiv, Ukraine, replicating and extending the original findings from a sample in Nashville, Tennessee (J. Garber et al. 1991).

The role of Alzheimer's disease-related presenilin 1 in intercellular adhesion.

Most cases of familial early-onset Alzheimer's disease are caused by mutations in the presenilin 1 (PS1) gene. However, the cellular functions of PS1 are unknown. We showed predominant localization of PS1 to cell-cell contacts of the plasma membrane in human prostate epithelial tissue and in a human epithelial cell line HEp2 stably transfected with an inducible PS1 construct.

Children's well-being 11 years after the Chornobyl catastrophe.

Background: The psychological effects of technological disasters have rarely been studied in children. This study assessed the aftermath of the 1986 Chornobyl disaster in children evacuated to Kyiv from the contaminated zone surrounding the nuclear power facility.

Methods: In 1997, we evaluated three hundred 10- to 12-year-old children in Kyiv who were in utero or infants at the time of the disaster and who had resided near Chornobyl (evacuees) and 300 sex-matched homeroom classmates who had never lived in a radiation-contaminated area.

School and neuropsychological performance of evacuated children in Kyiv 11 years after the Chornobyl disaster.

This paper examines the cognitive and neuropsychological functioning of children who were in utero to age 15 months at the time of the Chornobyl disaster and were evacuated to Kyiv from the 30-kilometer zone surrounding the plant. Specifically, we compared 300 evacuee children at ages 10-12 with 300 non-evacuee Kyiv classmates on objective and subjective measures of attention, memory, and school performance. The evacuee children were not significantly different from their classmates on the objective measures (grades; Symbolic Relations subtest of the Detroit Test; forms 1 and 2 of the Visual Search and Attention Test; Benton Form A; Trails A; Underline the Words Test) or on most of the subjective measures (the attention subscale of the Child Behavior Checklist completed by mothers; the attention items of the Iowa Conners Teacher's Rating Scale; mother and child perceptions of school performance).

Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells.

Pathological degeneration of neurons in Huntington's disease and associated neurodegenerative disorders is directly correlated with the expansion of CAG repeats encoding polyglutamines of extended length. The physical properties of extended polyglutamines and the intracellular consequences of expression of polyglutamine expansion have been the object of intensive investigation. We have extended the range of lengths of polyglutamine produced by recombinant DNA methodology by constructing a library of CAG/CAA repeats coding for a range of 25-300 glutamine residues.

Endogenous presenilin 1 redistributes to the surface of lamellipodia upon adhesion of Jurkat cells to a collagen matrix.

Most familial early-onset Alzheimer's disease cases are caused by mutations in the presenilin 1 (PS1) gene. Subcellular localization of the endogenous PS1 is essential for understanding its function, interactions with proteins, and role in Alzheimer's disease. Although numerous studies revealed predominant localization of PS1 to endoplasmic reticulum and Golgi, there are conflicting reports on the localization of PS1 to the cell surface.

Binding of amyloid beta protein to the 20 S proteasome.

Neurodegenerative disorders of aging are characterized by the intraneuronal accumulation of ubiquitin conjugates into tangles and inclusions. Ubiquitin conjugates are degraded by cellular particles known as proteasomes. We have previously shown that amyloid beta protein (Abeta) inhibits proteasomal activity and thereby blocks ubiquitin conjugate degradation.

Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation.

Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles.

Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro.

Intraneuronal accumulation of ubiquitin conjugates in inclusion bodies and neurofibrillary tangles is a pathological feature of neurodegenerative disorders such as Alzheimer's disease and Down's syndrome and of normal aging of the brain. Amyloid beta-protein (A beta) and its precursor are found in neurofibrillary tangle-containing neurons. A beta is the major component of extracellular plaques.

USF binds to the APB alpha sequence in the promoter of the amyloid beta-protein precursor gene.

The APB alpha domain in the amyloid beta-protein precursor (APP) promoter contains a nuclear factor binding domain with the core recognition sequence TCAGCT-GAC. Proteins in nuclear extracts from brain and numerous cell lines bind to this domain and it contributes approximately 10-30% to the basal APP promoter activity. Included in this domain is the CANNTG motif, which is recognized by basic helix-loop-helix transcription factors.

Ubiquitin-mediated degradative pathway degrades the extracellular but not the intracellular form of amyloid beta-protein precursor.

The presence of ubiquitin and ubiquitin conjugates has been detected in patients affected by neurodegenerative diseases such as Alzheimer's disease. We investigated the role of ubiquitin in the degradation of amyloid beta-protein precursor (APP) and its participation in the process of amyloid beta-protein formation. APP was tested as a substrate for ubiquitin-mediated degradation, using both the extracellular and the intracellular forms of APP770, APP751 and APP695.

Complex genetic disease: can genetic strategies in Alzheimer's disease and new genetic mechanisms be applied to epilepsy?

Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using "reverse" or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in Charcot-Marie-Tooth disease (type 1A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues.

Binding of IgG to amyloid beta A4 peptide via the heavy-chain hinge region with preservation of antigen binding.

Amyloid beta A4 peptide is found in the extracellular region of the senile plaque and in the angiopathy of Alzheimer's disease. Several other proteins, including IgG, also reside in these abnormal structures. In an attempt to understand how these structures are assembled and to determine how proteins are recruited, interactions of various proteins with synthetic beta A4 peptide have been examined in vitro.

Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.

Amyloid beta-peptide (A beta) deposition in senile plaques and cerebral vessels is a neuropathological feature of Alzheimer disease (AD). We examined the possibility that commonly observed variability in A beta deposition in late-onset AD might be related to apolipoprotein E genotype (APOE gene; the two most common alleles are 3 and 4), since APOE4 is a susceptibility gene for late-onset AD and apolipoprotein E interacts strongly with A beta in vitro. In an autopsy series of brains of late-onset AD patients, we found a strong association of APOE4 allele with increased vascular and plaque A beta deposits.