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PubMed1991

Straightbred comparison of a composite population and the Suffolk breed for performance traits of sheep.

A terminal sire Composite population was formed by mating Columbia rams to Hampshire-Suffolk crossbred ewes. Subsequent generations were produced by inter se mating. The objective was to compare Composite sheep to purebred Suffolks for numerous performance traits. Young ewes lambing at 1 yr of age were evaluated separately from mature ewes (2, 3, 4, and 5 yr old) of each population. Composite and Suffolk populations did not differ significantly in components of litter weaning weight per young ewe joined. Mature Composite ewes produced more wool than Suffolk ewes. Fertility of mature ewes did not differ significantly between populations. The greater prolificacy (P less than .01) of mature Suffolk ewes was offset by a lower survival to weaning (P less than .01), particularly for twin-born lambs. Consequently, mature Composite and Suffolk ewes did not differ for number weaned and litter weaning weight per ewe joined. The average birth weight of lambs born to young and mature Composite ewes was greater (P less than .02) than the average birth weight of Suffolk lambs. The average weaning weight of lambs born to young Composite ewes was greater (P less than .05) than that of lambs born to young Suffolk ewes. Breed differences were not detected for preweaning daily gains, weaning weights, and postweaning daily gains of ewe lambs born to mature ewes. Likewise, weights of ewes at 125 d of age and weights of mature ewes at breeding did not differ significantly between breeds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Soybean genomic survey: BAC-end sequences near RFLP and SSR markers.

We are building a framework physical infrastructure across the soybean genome by using SSR (simple sequence repeat) and RFLP (restriction fragment length polymorphism) markers to identify BACs (bacterial artificial chromosomes) from two soybean BAC libraries. The libraries were prepared from two genotypes, each digested with a different restriction enzyme. The BACs identified by each marker were grouped into contigs. We have obtained BAC- end sequence from BACs within each contig. The sequences were analyzed by the University of Minnesota Center for Computational Genomics and Bioinformatics using BLAST algorithms to search nucleotide and protein databases. The SSR-identified BACs had a higher percentage of significant BLAST hits than did the RFLP-identified BACs. This difference was due to a higher percentage of hits to repetitive-type sequences for the SSR-identified BACs that was offset in part, however, by a somewhat larger proportion of RFLP-identified significant hits with similarity to experimentally defined genes and soybean ESTs (expressed sequence tags). These genes represented a wide range of metabolic functions. In these analyses, only repetitive sequences from SSR-identified contigs appeared to be clustered. The BAC-end sequences also allowed us to identify microsynteny between soybean and the model plants Arabidopsis thaliana and Medicago truncatula. This map-based approach to genome sampling provides a means of assaying soybean genome structure and organization.

Algorithms↗
PubMed1983

Yearling trait comparisons among inbred lines and selected noninbred and randomly bred control groups of Rambouillet, Targhee and Columbia ewes.

Inbreeding with concurrent selection was used to develop 26 Rambouillet, 20 Targhee and 10 Columbia inbred lines of sheep. Inbreeding coefficients averaged 30, 29 and 30% for the three breeds, respectively, at the conclusion of the study. A selected noninbred control group and a randomly bred unselected control group were maintained for each breed. Yearling traits were evaluated for 545 Rambouillet, 572 Targhee and 411 Columbia yearling ewes, each belonging to one of the inbred lines or control groups. In each breed, the selected controls were generally of greatest overall merit, the unselected controls intermediate and the inbred lines of least merit. Only a few yearling traits of only a few inbred lines were superior (P less than .05) to those of their appropriate selected control groups. Selection within inbred lines was generally ineffective in offsetting inbreeding depression. However, single trait selection for traits of high heritability, notably yearling weight, clean fleece weight and staple length, appeared to compensate for inbreeding effects on those traits. Deleterious consequences of inbreeding were particularly apparent in yearling weight, average daily gain, type and condition scores, grease and clean fleece weights and index of overall merit. Inbreeding also resulted in fewer neck folds among inbreds of all three breeds. Correlations between the rankings of inbred lines at weaning and yearling ages were high for traits of higher heritability. Superiority of the selected controls in most traits was of about the same magnitude at weaning and yearling ages. In no case did the final overall merit (index value) of an inbred line of any of the three breeds significantly exceed the overall merit of its respective selected control group.

Age Factors↗
PubMedDate not supplied

[Potentiation of metaphit-induced audiogenic epilepsy with N-methyl-D-aspartate in rats].

INTRODUCTION: Audiogenic seizures (AGS) are induced by high intensity sound stimulation in genetically susceptible rats or in animals subjected to chemical or electrical manipulation. Epileptic seizure may result from an impaired balance between excitation and inhibition in the CNS. The effect of NMDA (N-methyl-D-aspartic acid) on metaphit 1-(1(3-isothiocyanatophenyl-ciclohexyl)-piperidine) induced audiogenic seizures was evaluated in rats. METHODS: Male Wistar albino rats were divided into 4 groups: 1) saline; 2) metaphit (10 mg/kg); 3) metaphit + NMDA; 4) NMDA (70 mg/kg). Animals were injected with metaphit intraperitoneally (i.p.) and exposed to sound stimulation (100 +/- 3 dB, 60 s) at hourly intervals. The incidence and severity (running, clonus and tonus) of seizures were analyzed. NMDA alone was administered i.p. to 6 rats. In group metaphit + NMDA only animals which did not exhibit any seizure during 8 hours were injected with NMDA i.p. after the 8th audiogenic testing. For electroencephalograph (EEG) recordings three gold-plated screws were used. Convulsive behaviour was assessed by incidence of motor seizure and by seizure severity grade, determined by use of a descriptive rating scale with range of 0-3; 0-no response; 1-wild running only; 2-wild running followed by clonic seizures of all four limbs with body rollover; 3-wild running progressing to generalized clonic convulsions and then a tonic extension of the fore and hind limbs and tail. Sound onset, seizure events, and sound offset, along with the animals behaviour (convulsive or other) were recorded as the correlates to the respective EEG responses. RESULTS: In most animals the administration of metaphit (10 mg/kg) resulted in electrographic abnormalities, elicited epileptiform activity in the form of spikes, polyspikes and spikewave complexes (Fig. 1.). Maximum incidence and severity of metaphit convulsions occurred 8 h after the injection (9/12, 75%) (Fig. 2, 3.), then abated gradually and disappeared 30 h later. NMDA (70 mg/kg) alone induced no seizure response but isolated spiking activity, and sporadic slow-wave complexes were recorded (Fig. 4). NMDA induced stereotyped behaviour in the form of asymmetric posture, loss of righting reflex and tonic hindlimb extension, which lasted for 60-90 min. Subconvulsive dose of NMDA potentiated the metaphit-induced audiogenic seizures in rats. Two hours after NMDA administration 3 of 17 metaphit-treated rats convulsed, which in 8 previous testings never displayed seizures. Maximum incidence was 8 of 17 (53%), 5-6 h after NMDA administration and seizures lasted for 9 hours. DISCUSSION: Several authors reported that metaphit dose of 10 mg/kg accompanied by some REM sleep deprivation (REM-D) procedures [4], or subconvulsive doses of NMDA [25] provoked seizures of higher intensity and incidence. Metaphit treatment (10 mg/kg) followed 24 h later by NMDA dose of 50 mg/kg provoked no spontaneous convulsions, while metaphit in combination with a higher NMDA dose of 70 mg/kg resulted in spontaneous and AGS-induced seizures only in one time point [25]. It was found that the incidence and severity of convulsive responses were highest 8-12 h after metaphit injection (10 mg/kg) [23, 24]. Although about 8 h after metaphit administration the power spectra increased and were more intense in the period of sound onset and seizure events. CONCLUSION: The results of the present study strongly suggest that treatment of adult rats with the combination of metaphit and NMDA in the doses employed here followed by AGS provides a suitable animal model for examinations of epileptic seizures.

Acoustic Stimulation↗
PubMedDate not supplied

Structural determinants of vascular resistance properties in hypertension. Haemodynamic and model analysis.

The average internal radius (ri) of the resistance vessels of the hindquarter (HQ) bed was narrower in renovascular and genetic hypertension than in normotensive controls. The narrowing was approximately uniform over the full range of vasomotor tone, which accounted for the bed's property as an 'amplifier' of vascular resistance (R) (increased slope (S) of the dose-R response curve) and for the elevated R at maximum dilatation (Rmin). In the model we examined the effects on the dose-R curve parameters of altering wall/internal radius (w/ri) ratio, ri and wall 'stiffness' one at a time, whilst the others were held constant: only narrowing of ri led to increases in both S and Rmin; with hypertrophy alone, S increased but Rmin was reduced, whilst increased wall stiffness increased Rmin but lowered S. Thus, for hypertrophy to be associated with rises of both S and Rmin, it must be linked to lumen narrowing, to increased wall stiffness, or to both. Preferential deposition of new material towards the lumen will link hypertrophy to narrowing. It has been suggested that narrowing can occur without hypertrophy ('remodelling'). In the model an increase of only 1-2% WV was required to produce rises in w/ri of congruent to 30-50% when associated with congruent to 10-15% reduction in ri, which is close to the limit of detection. From the literature, the sites of greater narrowing in hypertension extend down to small arteries and large arterioles. The rise in BP upstream from those sites, due to the vascular amplifier, offsets the down-stream effects of vascular narrowing on blood flow and this negative feedback system helps to maintain elevation of BP at a stable level. We also examined developmental rise in R between 4 and 50 weeks, which affected SHR and WKY in the same proportion: structural factors (vascular length of larger arteries, 'rarefaction' of arterioles and capillaries) accounted for only about half the rise in R, and the remainder was probably due to developmental changes in muscle function.

Animals↗
PubMed2006

Selection on body size and sexual size dimorphism differs between host species in a seed-feeding beetle.

Sexual size dimorphism varies substantially among populations and species but we have little understanding of the sources of selection generating this variation. We used path analysis to study how oviposition host affects selection on body size in a seed-feeding beetle (Stator limbatus) in which males contribute large ejaculates (nuptial gifts) to females. Females use nutrients in these ejaculates for egg production. Male body size, which affects ejaculate size, affects female fecundity and is thus under fecundity selection similar in magnitude to the fecundity selection on female body size. We show that when eggs are laid on a host on which larval mortality is low (seeds of Acacia greggii) fecundity predicts fitness very well and fecundity selection is the major source of selection on both male and female adult size. In contrast, when eggs are laid on a host on which larval mortality is high (seeds of Parkinsonia florida) fecundity poorly predicts fitness such that fecundity selection is relaxed on both male and female size. However, because egg size affects larval mortality on this poor host (P. florida) there is selection on female size via the female size --> egg size --> fitness path; this selection via egg size offsets the reduction in fecundity selection on female, but not male, body size. Thus, differences in host suitability (due to differences in larval mortality) affect the relative importance of two sources of selection on adult body size; fecundity selection on both male and female body size is lower on the poor quality host (P. florida) relative to the high quality host (A. greggii) whereas selection on female body size via effects of egg size on offspring survival (body size --> egg size --> fitness) is greater on the poor quality host relative to the high quality host. Because selection via the egg size path affects only females the difference in larval survival between hosts shifts the relative magnitude of selection on female vs. male size. Researchers working on other study systems should be alerted to the possible importance of subtle, but consequential, indirect selection on their study organisms.

Animals↗
PubMed2005

Selection for plasmid post-segregational killing depends on multiple infection: evidence for the selection of more virulent parasites through parasite-level competition.

Is the virulence of parasites an outcome of optimized infection? Virulence has often been considered an inevitable consequence of parasite reproduction when the cost incurred by the parasite in reducing the fitness of its current host is offset by increased infection of new hosts. More recent models have focused on how competition occurring between parasites during co-infection might effect selection of virulence. For example, if co-infection was common, parasites with higher intrinsic growth rates might be selected, even at the expense of being optimally adapted to infect new hosts. If growth rate is positively correlated with virulence, then competition would select increased virulence. We tested these models using a plasmid-encoded virulence determinant. The virulence determinant did not contribute to the plasmid's reproduction within or between hosts. Despite this, virulent plasmids were more successful than avirulent derivatives during selection in an environment allowing within-host competition. To explain these findings we propose and test a model in which virulent parasites are selected by reducing the reproduction of competitors.

Animals↗
PubMed2006

Endothelial dysfunction and hypertension in rats transduced with CYP4A2 adenovirus.

Vascular cytochrome P450 (CYP) 4A enzymes catalyze the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid which participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor and myogenic stimuli. This study was undertaken to investigate the consequences of CYP4A overexpression on blood pressure and endothelial function in rats treated with adenoviral vectors carrying the CYP4A2 construct. Intravenous injection of Adv-CYP4A2 increased blood pressure (from 114+/-1 to 133+/-1 mm Hg, P<0.001), and interlobar renal arteries from these rats displayed decreased relaxing responsiveness to acetylcholine, which was offset by treatment with an inhibitor of CYP4A. Relative to data in control rats, arteries from Adv-CYP4A2-transduced rats produced more 20-HETE (129+/-10 versus 97+/-7 pmol/mg protein, P<0.01) and less nitric oxide (NO; 4.2+/-1.6 versus 8.4+/-1 nmol nitrite+nitrate/mg; P<0.05). They also displayed higher levels of oxidative stress as measured by increased generation of superoxide anion and increased expression of nitrotyrosine and gp91phox. Collectively, these findings demonstrate that augmentation in vascular 20-HETE promotes the development of hypertension and causes endothelial dysfunction, a condition characterized by decreased NO synthesis and/or bioavailability, imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, and enhanced endothelial activation.

Adenoviridae↗
PubMed1997

Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2.

OBJECTIVE: To study nonsyndromic progressive sensorineural hearing loss (SNHL) with significant linkage to the DFNA2 locus on chromosome 1p in a Dutch kindred. DESIGN: A 6-generation family with 194 family members was studied. Of the presumably affected persons, 43 were examined in detail to obtain audiograms and 37 underwent vestibulo-ocular examination. RESULTS: Regression analysis showed significant and equal linear progression in SNHL with age (by about 1 dB per year) at all frequencies. Offset values were close to zero at the low frequencies (0.25, 0.5, and 1 kHz) but increased systematically with the frequency. It is likely that they represent congenital high-frequency SNHL: about 15 dB at 2 kHz, 30 dB at 4 kHz, and 50 dB at 8 kHz. Bilateral caloric weakness was not observed. A significant finding was that 25% to 35% (depending on the exclusion criteria) of the patients showed an increased vestibulo-ocular reflex (hyperreactivity) as measured by rotatory responses. Forty-one patients showed significant linkage to the 1p locus. CONCLUSIONS: Including the present family, 4 families have been reported to show linkage to chromosome 1p. Statistical analysis of the audiological data shows a progression of 1 dB per octave per year in this type of progressive SNHL.

Adult↗
PubMed2006

Changes in plant mitochondrial electron transport alter cellular levels of reactive oxygen species and susceptibility to cell death signaling molecules.

Transgenic tobacco (Nicotiana tabacum) lacking mitochondrial alternative oxidase (AOX) have been compared with wild-type (Wt) tobacco using two different systems, either suspension cell cultures or leaves. In both systems, a lack of AOX was accompanied by an increase in some anti-oxidant defenses, consistent with the hypothesis that a lack of AOX increases the mitochondrial generation of reactive oxygen species (ROS). In most cases, this increase in anti-oxidant defenses could more than offset the presumed increased rate of ROS generation, resulting paradoxically in a lower steady-state level of ROS than was found in Wt leaves or suspension cells. We also found that the amount of cell death induced by salicylic acid or nitric oxide correlated strongly with the level of ROS (irrespective of the level of AOX), while death induced by azide was dependent upon the presence or absence of AOX. These results suggest that susceptibility to cell death by signaling molecules (salicylic acid and nitric oxide) is dependent upon the steady-state cellular level of ROS and that AOX levels clearly contribute to this steady state, perhaps by influencing the rate of mitochondrial-generated ROS and hence the cellular level of anti-oxidant defenses.

Antioxidants↗
PubMed2000

Non-syndromic autosomal dominant progressive non-specific mid-frequency sensorineural hearing impairment with childhood to late adolescence onset (DFNA21).

An autosomal dominant trait of progressive, non-syndromic, non-specific mid-frequency sensorineural hearing impairment was identified in a Dutch family. Many affected family members (n = 21) were identified, among whom seven out of nine relatives aged < 30 years do not show pure mid-frequency hearing impairment, which suggests variable expression. Regression analysis was used to evaluate the age-related hearing threshold data in a cross-sectional analysis in 24 affected patients and in a longitudinal analysis in five of these. At all frequencies, progression in hearing impairment (i.e. the regression coefficient) was significant and fairly similar: the pooled value was about 1.0 dB/y. There was no significant (i.e. not =0 dB) offset threshold (i.e. Y intercept at age 0) found at any frequency. The regression lines could be pooled for the low frequencies (0.25-0.5 kHz) and the mid/high frequencies (1-8 kHz) and this produced apparent onset ages of about 3 and 4 years and annual threshold increases of 0.75 and 1.1 dB/y, respectively. In most patients there is a relatively late onset age (maximum in the range of at least 25-45 years). However, based on the longitudinal analysis of a patient from the age of 4 years onwards in some patients sensorineural hearing impairment might be congenital/prelingual. Oculo-vestibular function was found to be normal. Results from linkage studies tentatively position the underlying gene defect telomeric to the repositioned DFNA13 locus at chromosome 6p21-22.

Adult↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2000

The evolution of dosage-compensation mechanisms.

Dosage compensation is the process by which the expression levels of sex-linked genes are altered in one sex to offset a difference in sex-chromosome number between females and males of a heterogametic species. Degeneration of a sex-limited chromosome to produce heterogamety is a common, perhaps unavoidable, feature of sex-chromosome evolution. Selective pressure to equalize sex-linked gene expression in the two sexes accompanies degeneration, thereby driving the evolution of dosage-compensation mechanisms. Studies of model species indicate that what appear to be very different mechanisms have evolved in different lineages: the male X chromosome is hypertranscribed in drosophilid flies, both hermaphrodite X chromosomes are downregulated in the nematode Caenorhabditis elegans, and one X is inactivated in mammalian females. Moreover, comparative genomic studies demonstrate that the trans-acting factors (proteins and non-coding RNAs) that have been shown to mediate dosage compensation are unrelated among the three lineages. Some tantalizing similarities in the fly and mammalian mechanisms, however, remain to be explained.

Animals↗
PubMed2006

Application of HSVtk suicide gene to X-SCID gene therapy: ganciclovir treatment offsets gene corrected X-SCID B cells.

Recently, a serious adverse effect of uncontrolled clonal T cell proliferation due to insertional mutagenesis of retroviral vector was reported in X-SCID gene therapy clinical trial. To offset the side effect, we have incorporated a suicide gene into therapeutic retroviral vector for selective elimination of transduced cells. In this study, B-cell lines from two X-SCID patients were transduced with bicistronic retroviral vector carrying human gamma c chain cDNA and Herpes simplex virus thymidine kinase gene. After confirmation of functional reconstitution of the gamma c chain, the cells were treated with ganciclovir (GCV). The gamma c chain positive cells were eliminated under low concentration without cytotoxicity on untransduced cells and have not reappeared at least for 5 months. Furthermore, the gamma c chain transduced cells were still sensitive to GCV after five months. These results demonstrated the efficacy of the suicide gene therapy although further in vivo studies are required to assess feasibility of this approach in clinical trial.

Antiviral Agents↗
PubMed2005

Offset recombinant PCR: a simple but effective method for shuffling compact heterologous domains.

DNA shuffling and other in vitro recombination strategies have proven highly effective at generating complex libraries for mutagenesis studies. While most recombination techniques employ DNA polymerases in part of a multi-step process, few seek to exploit the natural recombinogenic tendencies and exponential amplification rates of PCR. Here, we characterize a simple but effective method for using standard PCR to promote high recombination frequencies among compact heterologous domains by locating the domains near one end of the template. In a typical amplification reaction, Pfu polymerase generated chimeric crossover events in 13% of the population when markers were separated by only 70 nt. The fraction of recombinant sequences reached 42% after six consecutive rounds of PCR, a value close to the 50% expected from a fully shuffled population. When homology within the recombinant region was reduced to 82%, the recombination frequency dropped by nearly half for a single amplification reaction and crossover events were clustered toward one end of the domain. Surprisingly, recombination frequencies for template populations with high and low sequence homologies converged after just four rounds of PCR, suggesting that the exponential accumulation of chimeric molecules in the PCR mixture serves to promote recombination within heterologous domains.

DNA Shuffling↗
PubMed2026

A novel relationship between time offsets in capillary electrophoresis and DNA sequence variations in short tandem repeats.

Next-generation sequencing (NGS) provides increased discriminatory power in forensic DNA analysis due to the detection of isoalleles. Differences in sequences between alleles allow for a second layer of differentiation between DNA contributors beyond the number of short tandem repeat (STR) repeat units. However, because NGS is a more time and resource-intensive analysis than conventional capillary electrophoresis (CE), laboratories may benefit from indicators that suggest NGS is likely to provide added value. This study examined whether CE migration offsets, measured as residuals in the OSIRIS analysis software, can differ significantly among STR isoalleles. Residuals represent the time offset between a sample allele peak and its corresponding allelic ladder peak. Paired CE and NGS data from 95 single source samples were analyzed for CE-based residual differences, as the NGS data provided the sequence information of the corresponding isoalleles. Residual values differed significantly among isoalleles at several STR loci. Statistically significant differences were identified at D16S539 and D3S1358, as well as at specific allele lengths within D12S391, D13S317, and D8S1179. These findings demonstrate that CE residual variation can reflect underlying STR sequence differences between contributors. In practice, residual-based metrics could help laboratories to identify casework reference samples where NGS is likely to provide additional discrimination, without the need for processing outside of a routine CE workflow. Due to the potentially large number of isoalleles, community wide efforts to aggregate CE residual differences versus isoallele sequences may be useful in the validation and implementation of this approach to add value to forensic DNA analyses.

Electrophoresis, Capillary↗
PubMed2006

Parental investment by skin feeding in a caecilian amphibian.

Although the initial growth and development of most multicellular animals depends on the provision of yolk, there are many varied contrivances by which animals provide additional or alternative investment in their offspring. Providing offspring with additional nutrition should be favoured by natural selection when the consequent increased fitness of the young offsets any corresponding reduction in fecundity. Alternative forms of nutrition may allow parents to delay and potentially redirect their investment. Here we report a remarkable form of parental care and mechanism of parent-offspring nutrient transfer in a caecilian amphibian. Boulengerula taitanus is a direct-developing, oviparous caecilian, the skin of which is transformed in brooding females to provide a rich supply of nutrients for the developing offspring. Young animals are equipped with a specialized dentition, which they use to peel and eat the outer layer of their mother's modified skin. This new form of parental care provides a plausible intermediate stage in the evolution of viviparity in caecilians. At independence, offspring of viviparous and of oviparous dermatotrophic caecilians are relatively large despite being provided with relatively little yolk. The specialized dentition of skin-feeding (dermatophagous) caecilians may constitute a preadaptation to the fetal feeding on the oviduct lining of viviparous caecilians.

Amphibians↗
PubMed2001

Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

Aging↗