Long term changes in phospho-APP and tau aggregation in the 3xTg-AD mice following cerebral ischemia.

The risk of Alzheimer's disease increases following cerebral hypoperfusion. We studied the long-term interaction between low blood flow to the brain and Alzheimer's disease by inducing a transient global ischemic insult in aged 3xTg-AD mice and determining the effects on AD pathology 3-months post injury. We found that global ischemia does not increase the levels of amyloid-ß in these mice. However, the injury did lead to enhanced phosphorylation of the amyloid precursor protein (APP) at the Thr668 site in both the 3xTg-AD mice and wild-type controls. Furthermore, we found an increase in insoluble total tau 3-months post-injury. Together these findings further elucidate the long-term impact of cerebral hypoperfusion on Alzheimer's disease.

Differential expression of fibronectin receptors during myeloid differentiation and in marrow- and peripheral blood-derived leukemic cells.

A 125I-labeled 120-kDa fibronectin fragment (FN120) containing the RGD binding site was employed to assess FN120 receptor levels in control and dimethylsulfoxide (DMSO)-differentiated HL60 cells, as well as in leukemic peripheral and bone marrow blast cells from acute lymphoid (ALL) and myeloid (AML) patients. Fibronectin CS1 fragment receptor alpha 4 (VLA4-alpha) and RGD-dependent alpha 5 integrin subunits (VLA5-alpha) were characterized by specific monoclonal antibodies (MoAb). HL60 cells, induced along the granulocytic pathway with DMSO, displayed low FN120 binding level densities (36,070 +/- 5142 sites/cell (s/c) vs. 19,780 +/- 4564 s/c, P < 0.005), respectively, for untreated and treated cells) together with decreased VLA5-alpha expression. Granulocytes displayed low levels of FN120 receptors (3167 +/- 1165 s/c) with weak VLA5-alpha expression and absence of VLA4-alpha. Normal lymphocytes displayed 17,670 +/- 8,705 s/c FN120 receptors and VLA4-alpha and VLA5-alpha. The mean FN120 binding levels and mean VLA5-alpha expression were lower in peripheral blast cells, both in ALL and AML, than in the bone marrow leukemic cells. VLA4-alpha remained the same irrespective of cell localization. FN120 binding sites and differential expression of VLA4-alpha and VLA5-alpha integrin molecules on hemopoietic cells could be related to lineage characteristics or cell type distribution within hemopoietic tissue.

Vitamin D3 binding activity during leukemic cell differentiation.

In this paper we report that differentiation of the human promyelocytic leukemia cell line, HL60, along the myelocytic pathway, induced by retinoic acid (RA), or monocytic pathway, induced by phorbol-myristate acetate (PMA) and gamma interferon (IFN), was accompanied by a significant decline in 1,25-dihydroxycholecalciferol (1,25(OH)2D3) binding (control: 30.3 +/- 3.0 fM/10(6) cells; RA treated: 6.8 + 2.5 fM/10(6) cells; PMA treated: 12.3 +/- 6.7 fM/10(6) cells and IFN treated: 16.0 +/- 5.0 fM/10(6) cells). When differentiation and proliferation were uncoupled, by incubation with IFN or by inhibition of proliferation by cell density saturation, 1,25(OH)2D3 binding was better related to differentiation than to proliferation. Additionally we have compared 1,25(OH)2D3 binding levels in blasts from acute lymphocytic leukemia (ALL) patients (25.4 +/- 18.1 fM/10(6) cells) and normal, mature lymphocytes (10.6 +/- 2.1 fM/10(6) cells). Receptor binding was significantly higher (p < 0.05) in the immature blasts. Our data suggest that 1,25(OH)2D3 receptor levels could be considered a marker of functional immaturity, in these cells.