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An analysis of the possible effect of long-term stress from radiation exposure on cognitive functioning in 300 children from families evacuated to Kyiv, Ukraine, following the Chornobyl nuclear power plant accident in 1986 indicates that the evacuee children performed as well as their contemporaries in memory, attention and intelligence tests. This was also the case for children who were in utero at the time of the disaster. However, more evacuee mothers reported memory difficulties in their children than classmates' mothers. This is likely to be connected with mothers' anxiety.

Addition of amyloid beta protein (Abeta) to cerebrospinal fluid (CSF) of patients with Alzheimer's disease and normals reveals that transthyretin (TTR), a CSF protein, sequesters Abeta protein into stable complexes. Sequestration prevents aggregation of Abeta proteins leading to amyloid fibrils, which are associated with Alzheimer disease. In vitro studies show that apolipoprotein E does not complex with Abeta in CSF.

The binding of synthetic amyloid beta (beta/A4) peptide was compared to purified apolipoprotein E4 (apoE4) and the most common isoform, apoE3, to find if apoE4 is related to enhanced vulnerability to Alzheimer disease. The two isoforms form a complex with the beta/A4 peptide in different ways. ApoE is regionalized in the senile plaques, congophilic angiopathy and neurofibrillary tangles of Alzheimer disease.

Localization of Amyloid Protein Messenger RNA in Brains from Patients with Alzheimer's Disease WE HAVE USED THE COMPLEMENTARYDNA (cDNA) clone Am4 (1) encoding amyloid protein (1-4) as a template to [...]

Amyloid Gene Duplication in Alzheimer's Disease and Karyotypically Normal Down Syndrome A COMPLEMENTARY DNA (cDNA)probe Am4 for the chromosome 21 gene encoding the amyloid polypeptide ( amyloid protein) of Alzheimer's [...]

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. I had to look at the papers of other researchers to make sure that my spelling was correct. After the cloning, I was invited to numerous national and international meetings on AD. These meetings became my University where I majored in AD. [ABSTRACT FROM AUTHOR]

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 β-protein (Aβ). Neuropathological and genetic studies provide strong evidence of a key role for Aβ amyloidosis in the pathogenesis of AD. Therefore, an obvious pharmacological target for treatment of AD is the inhibition of amyloid growth and/or inhibition of amyloid function. We took an unbiased approach to generate new inhibitors of amyloid formation by screening a FliTrx™ combinatorial peptide library for Aβ binding peptides and identified four groups of peptides with different Aβ binding motifs. In addition, we designed and examined peptides mimicking the Aβ binding domain of transthyretin (TTR). Our results showed that Aβ binding peptides selected from FliTrx™ peptide library and from TTR-peptide analogs are capable of inhibiting Aβ aggregation and Aβ deposition in vitro. These properties demonstrate that binding of selected peptides to the amyloid β-protein may provide potent therapeutic compounds for the treatment AD. [ABSTRACT FROM AUTHOR]

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 (Aβ) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear. To understand how TTR mutations influence the ability of TTR to inhibit Aβ amyloidosis, forty-seven recombinant TTR variants were produced and analyzed. We showed that all recombinant proteins formed tetramers and were functional in thyroxine binding. Acid denaturation at pH 3.8 resulted in aggregation and fibril formation of all TTR variants. However, only TTR G42 and TTR P55 formed fibrils at pH 6.8. Most TTR variants bound to Aβ and inhibited Aβ aggregation in vitro. TTR variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to Aβ and decreased inhibition of Aβ aggregation. Only TTR G42 and TTR P55 completely failed to bind Aβ and to inhibit Aβ aggregation. We suggest that TTR variants characterized by decreased binding to Aβ or by decreased inhibition of Aβ aggregation in vitro may contribute to Aβ amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

With the recently cloned complementary DNA probe, λAm4 for the chromosome 21 gene encoding brain amyloid polypeptide (l amyloid protein) of Alzheimer's disease, leukocyte DNA from three patients with sporadic Alzheimer's disease and two patients with karyotypically normal Down syndrome was found to contain three copies of this gene. Because a small region ofchromosome 21 containing the ets-2 gene is duplicated in patients with Alzheimer's disease, as weli as in karyotypically normal Down syndrome, duplication ofa subsection ofthe critical segment ofchromosome 21 that is duplicated in Down syndrome may be the genetic defect in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

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 SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment. [ABSTRACT FROM AUTHOR]

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., Objectives: To determine the effects of induced hyperinsulinemia with euglycemia on Abeta, transthyretin, and inflammatory markers and modulators in plasma and cerebrospinal fluid (CSF)., Design: Randomized crossover trial., Setting: Veterans Affairs hospital clinical research unit., Participants: Sixteen healthy adults ranging from 55 to 81 years of age (mean age, 68.2 years)., Interventions: On separate mornings, fasting participants received randomized infusions of saline or insulin (1.0 mU.kg(-1).min(-1)) with variable dextrose levels to maintain euglycemia, achieving plasma insulin levels typical of insulin resistance. Plasma and CSF were collected after an approximately 105-minute infusion., Main Outcome Measures: Plasma and CSF levels of interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, F2-isoprostane (CSF only), Abeta, norepinephrine, transthyretin, and apolipoprotein E., Results: Insulin increased CSF levels of F2-isoprostane and cytokines (both P<.01), as well as plasma and CSF levels of Abeta42 (both P<.05). The changes in CSF levels of Abeta42 were predicted by increased F2-isoprostane and cytokine levels (both P<.01) and reduced transthyretin levels (P = .02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (both P<.05)., Conclusion: Moderate hyperinsulinemia can elevate inflammatory markers and Abeta42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.