Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits

Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer’s disease (AD). It can occur before significant Aβ deposition and appears to “spread” into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here.     

Experimental chemotherapy of radiation injury with synthetic lysophospholipid analogs in mice

Synthetic lysophospholipids represent a variety of analogs of the naturally occurring 2-lysophosphatidylcholine. Some of these compounds showed significant therapeutic effects on the survival of mice following radiation injury when administered after various doses of whole-body X irradiation. Such therapeutic effects were discernible even when the treatment was given 6 hr after irradiation, and both intravenous and oral application were effective. Intravenous application of 2 X 25 mg/kg lysophospholipid after whole-body X irradiation around the LD50 resulted in significantly higher numbers of surviving animals. The mode of action remains speculative.     

Induction of an anti-hepatitis B surface antigen response in mice by noninternal image (Ab2 alpha) anti-idiotypic antibodies

Anti-idiotype antibodies to a mouse monoclonal antibody A-12 directed against HBsAg were produced in rabbits. The anti-Id consisted of an Ab-2 alpha preparation that did not display any detectable internal image activity. Immunization of BALB/c mice with the anti-Id (Ab-2 alpha) coupled to KLH induced an anti-HBs response without subsequent HBsAg exposure. No anti-HBs was detected in control groups of mice immunized with other rabbit anti-Id-KLH preparations. The anti-HBs containing sera from mice immunized with the Ab-2 alpha were able to inhibit the Id-anti-Id reaction, indicating that an Id-positive, anti-HBs response was induced. This idiotype is not normally expressed during the murine immune response to HBsAg and suggests that noninternal image anti-Id activates silent clones. This study, along with our previous results obtained with the use of internal image anti-Id, suggests that there is more than one Id network operational during the BALB/c murine immune response to HBsAg.     

The effect of hypercholesterolemia on guinea pig platelets, erythrocytes and megakaryocytes

This study has examined the effect of diet-induced hypercholesterolemia on guinea pig platelets, erythrocytes, megakaryocytes and plasma. The cholesterol/phospholipid ratios of plasma and erythrocytes began to increase after one day on the diet and increased steadily for two weeks and more slowly thereafter until 30 days. In contrast, the cholesterol/phospholipid ratio of platelets remained constant for 4-5 days, then increased until reaching a maximum of about 0.85 in two weeks. Thus, the time-course for increase of the cholesterol/phospholipid ratio is different for platelets than for erythrocytes and plasma. The increase in the cholesterol/phospholipid ratio of megakaryocytes was small and not dependent on the degree of increase in the plasma cholesterol/phospholipid ratio. The cholesterol esters of both platelets and megakaryocytes increased with time for two weeks. The increase in megakaryocyte cholesterol esters appeared to precede that of platelets. The protein content of platelets and megakaryocytes and average megakaryocyte size were increased. Normal platelets incubated in plasma from hypercholesterolemic guinea pigs did not accumulate excess cholesterol, but erythrocyte cholesterol increased 45% in 6 h under the same conditions. Cholesterol synthesis in megakaryocytes was depressed 50-80% by cholesterol feeding and by in vitro incubation of the cells in hypercholesterolemic plasma. The data suggest that the platelets and erythrocytes may accumulate excess cholesterol by different mechanisms. The effects of cholesterol feeding on megakaryocytes and the lag in accumulation of cholesterol in platelets relative to erythrocytes and plasma suggest that a defect in the megakaryocyte may be a primary determinant of accumulation of cholesterol in platelets.     

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The effect of temperature on unsaturated fatty acid loss in Tetrahymena pyriformis.

Cultures of Tetrahymena pyriformis W incorporate exogenous 3-[14C]-cilienic acid and gamma-[1(-14)C] linolenic acid, terminal products of unsaturated fatty acid synthesis, into glycerophosphatides without randomization of the radiolabel. There was no difference in the rate of loss of each of the two acids at 15 or 28.5 degrees C. Differential turnover of these fatty acids, therefore, does not appear to be the cause of the shift in fatty acid pattern observed with temperature reduction.     

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