Vitamin E in aging persons with Down syndrome: A randomized, placebo-controlled clinical trial.

OBJECTIVE: To determine whether vitamin E would slow the progression of cognitive deterioration and dementia in aging persons with Down syndrome (DS). METHODS: A randomized, double-blind controlled clinical trial was conducted at 21 clinical sites, and researchers trained in research procedures recruited adults with DS older than 50 years to participate. Participants were randomly assigned to receive 1,000 IU of vitamin E orally twice daily for 3 years or identical placebo. The primary outcome was change on the Brief Praxis Test (BPT). Secondary outcomes included incident dementia and measures of clinical global change, cognition, function, and behavior. RESULTS: A total of 337 individuals were randomized, 168 to vitamin E and 169 to placebo. Both groups demonstrated deterioration on the BPT with no difference between drug and placebo. At baseline, 26% were diagnosed with dementia and there was an overall rate of incident dementia of 11%/year with no difference between groups. There was no effect on the secondary outcome measures. Though numerically higher in the treatment group, there was no difference in the number of adverse events (p = 0.079) and deaths (p = 0.086) between groups. CONCLUSIONS: Vitamin E did not slow the progression of cognitive deterioration in older individuals with DS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that vitamin E does not significantly slow the progression of cognitive deterioration in aging persons with DS.

The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability.

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.

Snx3 regulates recycling of the transferrin receptor and iron assimilation.

Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.

Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis.

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1b. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1aa and gfi1b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors.

What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population?

The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of ß-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. With increasing sophistication in genetic experimental techniques, additional mechanisms associated with excessive amyloid deposits were postulated and tested in brains of people with Down syndrome and Alzheimer's disease and in those with early-onset Alzheimer's disease. This in turn led to the proposal and testing for particular genetic defects associated with familial early-onset Alzheimer's disease. Nearly 200 genetic causes of early-onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease.

The relationship of plasma Abeta levels to dementia in aging individuals with Down syndrome.

To study the relationship between plasma levels of amyloid beta (Abeta) peptides and dementia in aging individuals with Down syndrome, we investigated the relationship among plasma Abeta, apolipoprotein E genotype and cognitive and clinical factors using baseline specimens form participants in an ongoing clinical trial in individuals with Down syndrome 50 years of age and older. Because of substantial skew in the distribution of peptide levels, analyses used log transformations of the data. The ratio of Abeta42 to Abeta40 was associated with the presence of dementia (P=0.003, df=196, F=9.37); this association persisted after adjustment for age, sex level of mental retardation, and apolipoprotein E genotype. Consistent with recent reports regarding the effect of presenilin mutations on peptide generation, our finding supports the theory that the ratio of Abeta42 to Abeta40 rather than absolute levels of the peptides is important to the pathophysiology of Alzheimer's disease in genetically susceptible populations.

Increased serum neopterin levels in adults with Down syndrome.

We quantitated serum neopterin levels in Down syndrome (DS), normal controls, Alzheimer's disease, multiple sclerosis and other neurological diseases. We then analyzed the relationships with age, sex, apolipoprotein E (Apo E) phenotype, and amyloid beta protein 1-40 (Abeta40) and 1-42 (Abeta42) levels. Neopterin levels were higher in DS than all other groups. Levels in young DS (< 40 years of age) and old DS (> 41 years) were similar. There was no significant correlation between neopterin levels and age, sex, Apo E phenotype, and Abeta40 or Abeta42 levels in DS. This lack of correlation between neopterin and Abeta levels suggests that the higher neopterin concentrations in DS group reflect inflammatory cell activation rather than AD neuropathology.

Relation between apolipoprotein E genotype, hepatitis B virus status, and thyroid status in a sample of older persons with Down syndrome.

Dementia of the Alzheimer type (DAT) is common in older persons with Down syndrome (DS). There are three common alleles of the apolipoprotein E (ApoE) gene (Sigma 2, Sigma 3, and Sigma 4) resulting in three different isoforms (E2, E3, and E4) and six different genotypes (2,2; 2,3; 2,4; 3,3; 3,4; and 4,4). Sigma 4 is a risk factor for DAT whereas Sigma 2 appears prophylactic. As hepatitis B virus (HBV) infection and hypothyroidism also are common in DS, we evaluated associations between ApoE type, HBV status, and thyroid status in a sample of older persons with DS (n = 55; mean age, 44.3 +/- 10.8 years) using chi-squared analysis. Participants were classified as E2 (2,2 or 2,3), E3 (3,3), or E4 (3,4 or 4,4); positive for markers of HBV infection in the present or past (i.e., total HBcAb+ and/or HBsAg+ with or without infectivity, defined as HBV+) or negative for markers of HBV infection (defined as HBV-) and, currently receiving thyroid hormone supplement (defined as "hypothyroidism") or having normal thyroid function. The majority of the HBV+ were currently HBcAb+ and HBsAb+, but not HBsAg+. In females, there was an ApoE allele effect on thyroid status (P < or = 0.01), E2 being negatively (P < or = 0.01) and E4 being positively (P < or = 0.05) associated with "hypothyroidism". There was no evidence for an ApoE allele effect on thyroid status in males. There was no evidence for an ApoE allele effect on HBV status, or for an HBV status effect on thyroid status. As thyroid status can affect cognitive function, ApoE allele effects in DAT may, in part, be thyroid effects.

Plasma amyloid beta protein 1-42 levels are increased in old Down Syndrome but not in young Down Syndrome.

Plasma amyloid beta protein 1-40 (Abeta40) and Abeta42 levels were quantitated from 28 young Down syndrome (DS) (20-40 years old), 28 age-matched controls, 32 old DS (41-65 years old) and 32 age-matched controls in a sandwich enzyme-linked immunosorbent assay. Abeta40 levels were higher in young DS and old DS than controls. Abeta42 levels in young DS and controls were similar, however Abeta42 levels were higher in old DS than controls or young DS. The higher Abeta42 levels in old DS suggests that Abeta42 is selectively increased in plasma concurrently with the development of Alzheimer disease neuropathology.