A mini review: Tau transgenic mouse models and olfactory dysfunction in Alzheimer's Disease.

Alzheimer's Disease (AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment (MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss (1) the function of Tau physiologically and pathologically; (2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice; (3) the structural and molecule basis of olfaction; (4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction.

[Change of memory function and decrease of nitric oxide level of whole brain in the transgenic mice expressing human tau 40 with P301L mutation].

OBJECTIVE: To study the mechanism of learning and memory dysfuction in the transgenic mouse expressing human tau 40 isoform with P301L mutation (F10). METHODS: The human tau protein expression and phosphor-tau protein levels were detected with Western blot method. The neurofibrillary tangles were observed with Bielshowsky silver stain. The behavior changes of learning and memory were observed by open field test and passive avoidance test. Acetyleholine level, activities of acetycholinesterase and choline acetyltransferase of whole brain was detected by colorimetry method. The nitric oxide level of whole brain was detected by nitrate enzyme reduction method. RESULTS: Exogenous human tau gene was expressed and an elevation of phosphor-tau protein level in 7 and 3-month transgenic mice's hippocampus andcerebrocortex was observed. The neurofibrillary tangles were observed in cerebrocortex of 7-month transgenic mice; the 7-month transgenic mice also presented an evident reduction of learning and memory ability and nitric oxide level of the whole brain, but not changes in acetylcholine level, acetycholinesterase activity, choline acetyltransferase activity and expression in whole brain. CONCLUSION: Tau transgenic mice (F10) can still inherit their parents' biologiccal characters, and develop learning and memory dysfunction awnodh san obvious decrease in nitric oxide level of whole brain in the 7-month old mice, suggesting a decrease of nitric oxide level of whole brain would be involved in the mechanism of learning and memory dysfunction in these transgenic mice.

[Effect of hypobaric hypoxia exposure on memory and tau phosphorylation in brain of mice].

OBJECTIVE: To investigate the effect of hypobaric hypoxia (HH)on the cognitive function of mice and the phosphorylation of tau protein in mice brain. METHODS: Forty male mice were randomly divided into 4 groups (n = 10): static control (control) group, 8 hours (8 h) group, 7 days(7 d) group and 28 days(28 d) group, which were exposed to simulated HH equivalent to 5 500 m in an animal decompression chamber for 0 hour, 8 hours, 7 days and 28 days, respectively. Cognitive performances were examined by open field and passive avoidance test, tan phosphorylation was assayed by Western blot. RESULTS: In open field test,the group exposed in hypobaric hypoxia for 28 d showed lower mean velocity (P < 0.05), time in central zone (P < 0.05) was longer than control group. In passive avoidance test 28 d group presented worse performance in both latency time and number of mistakes (P < 0.05) compared with control group. Western blot showed that phosphorylated tau was increased significantly following exposure to HH for 7 d in cortex and 28 d in hippocampus (P < 0.05). CONCLUSION: Tau hyperphosphorylation in brain of mice may play a role in chronic HH-induced cognitive function impairment.

[Generation of Tau/App/PS1 triple-transgenic mouse model and the study of its biological characteristics].

OBJECTIVE: To establish the triple-transgenic mouse model and study their biological characteristics by molecular biology, behavior and pathology. METHODS: Hybrid the Tau and amyloid precursor protein (APP)/presenilins (PS1) transgenic mouse, the genotype of offspring mice were identified by PCR. Transcribed target genes were detected by RT-PCR. The protein expression of exogenous genes was detected by Western-blot. The pathological change of neurofibrillary tangles and senile plaque were observed by Bielschowsky silver staining and ABC immunohistochemical method. The changes time of learning and memory were observed by Morris water maze. RESULTS: APP, PS1 and Tau genes were transcript in Tau/APP/PS1 mice. In 6 to 8 months old Tau/APP/PS1 mice, the neurofibrillary tangles and senile plaque could be found in cortex and hippocampus. In 6 months old Tau/APP/PS1 mice, the learning and memory abilities were worse. CONCLUSION: With the behavior change and pathological changes in Tau and beta-amyloid protein (AP), the Tau/APP/PS1 triple-transgenic mice can be used as a further study animal model of AD's pathogenesis and the target of drug treatment.

[Breeding of transgenic mice expressing human tau isoform with P301L mutation and identification of homozygous transgenic mice].

OBJECTIVE: To establish homozygous transgenic mouse strain expressing human tau isoform with P301L mutation. METHODS: Five transgenic mice expressing human tau isoform with P301L mutation were obtained by microinjection into male nuclei. Homozygote and hemizygote were identified by PCR and real-time fluorescent quantitative PCR. RESULTS: Ninety five homozygous transgenic mice were selected, and the results indicated that homozygous transgenic mice were superior to hemizygote in simulating the changes of biological characteristics. CONCLUSION: Exogenous gene tau is able to stably transmit to next generation and the combination of SYBR Green real-time fluorescent quantitative PCR with the traditional mating is a fast, reliable and economical way to screen homozygous and hemizygous transgenic mice.

Similar potency of catechin and its enantiomers in alleviating 1-methyl-4-phenylpyridinium ion cytotoxicity in SH-SY5Y cells.

OBJECTIVES: Previously, the flavonoid (±)-catechin was shown to exert potent neuroprotective action in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease model. The purpose of this study was to investigate whether the different enantiomers of catechin ((+)-catechin, (-)-catechin and (±)-catechin, a 50:50 mixture of (+)-catechin and (-)-catechin) could protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP(+) ) toxicity by decreasing the generation of oxygen free radicals. The inhibitive effect of (±)-catechin on JNK/c-Jun activation was investigated. METHODS: The effects of (+)-catechin, (-)-catechin or (±)-catechin in protecting against MPP(+) toxicity were evaluated and compared in SH-SY5Y cells by testing the release of lactate dehydrogenase. The generation of reactive oxygen species (ROS) was measured by immunochemistry and the phosphorylation level of JNK/c-Jun was determined by Western blotting. KEY FINDINGS: In SH-SY5Y cells, (+)-catechin, (-)-catechin or (±)-catechin reduced apoptosis induced by MPP(+) and decreased ROS generation caused by MPP(+) . Different enantiomers of catechin showed protective effects at similar potency. Moreover (±)-catechin decreased JNK/c-Jun phosphorylation which was increased by MPP(+). CONCLUSIONS: Catechin and its two enantiomers could protect SH-SY5Y cells against MPP(+) cytotoxicity at a similar potency. Antioxidative stress and inhibition of the JNK/c-Jun signalling pathway might have been involved in the neuroprotective mechanisms of catechin against MPP(+) cytotoxicity in SH-SY5Y cells.

Down-regulation of peroxisome proliferator-activated receptor γ coactivator-1α expression in fatty acid-induced pancreatic beta-cell apoptosis involves nuclear factor-κB pathway.

BACKGROUND: Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to study the effects of palmitic acid (PA) on the apoptosis and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression in ßTC3 cells as well as the possible role of nuclear factor-κB (NF-κB) in this process. METHODS: Hoechst 33258 was used to detect ßTC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1α expression was analyzed by reverse transcription polymerase chain reaction, IκB kinase ß (IKKß), IκBα, NF-κB-inducing kinase (NIK) and Rel-B expressions were analyzed by Western blotting. MG132 was employed to block the endogenous IκBα degradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1α mRNA expression was analyzed. RESULTS: Significant increased cell apoptosis was found at the concentration of 0.5 mmol/L and 1.0 mmol/L PA administration. PA (0.5 mmol/L) could extensively reduced the expression of PGC-1α mRNA. After exposing ßTC3 cells to 0.5 mmol/L PA for different time periods (0, 4, 6, 8, 10 and 12 hours), IKKß protein expression increased while IκBα, NIK and Rel-B protein expression declined in a time-dependent manner. Pretreatment with MG132 to inhibit the degradation of IκBα, partially prevented the down-regulation of PGC-1α mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis. CONCLUSIONS: NF-κB canonical pathway was activated in PA-mediated ßTC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1α expression by PA in ßTC3 cells could involve the activation of canonical NF-κB pathway, so as to deteriorate the PA induced apoptosis.

[Isolation and identification of Suavissimoside R1 from roots of Rubus parvifollus used for protecting dopaminergic neurons against MPP+ toxicity].

OBJECTIVE: Suavissimoside R1 was isolated and identified as an active ingredient from Roots of Rubus parvifollus L, which exhibited protective effect on dopaminergic neurons against MPP+ toxicity. METHODS: The protective effects of crude extracts were investigated after mice were treated with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). According to the protective effects of crude extracts, suavissimoside R1, one kind of triterpenoid saponin, was separated. It was investigated that whether Suavissimoside R1 can protect DA neurons from toxicity induced by MPP+ in rat mesencephalic cultures. RESULTS: Suavissimoside R1 was isolated from Roots of Rubus parvifollus L. Moreover, Suavissimoside R1, in dose of 100 micromol/L, alleviated the death of DA neurons induced by MPP+ obviously. CONCLUSION: These results suggest that suavissimoside R1 possesses potent neuroprotective activity and can be developed to be a potential anti-Parkinson's disease drug worthy for further study.

Noradrenaline release by activation of κ-bungarotoxin-sensitive nicotinic acetylcholine receptors participates in long-term potentiation-like response induced by nicotine.

Nicotine enhances the function of learning and memory, but the underlying mechanism still remains unclear. Hippocampal long-term potentiation (LTP) is assumed to be a cellular mechanism of learning and memory. Our previous experiments showed that with the single pulses evoking 80% of the maximal population spike (PS) amplitude, nicotine (10 µmol/L) induced LTP-like response in the hippocampal CA1 region. In the present study, the nicotinic acetylcholine receptor (nAChR) subtypes and relevant neurotransmitter releases involved in LTP-like response induced by nicotine were investigated by extracellularly recording the PS in the pyramidal cell layer in the hippocampal CA1 region in vitro. LTP-like response induced by nicotine was blocked by mecamylamine (1 µmol/L) or κ-bungarotoxin (0.1 µmol/L), but not by dihydro-ß-erythtroidine (DHßE, 10 µmol/L). Moreover, it was inhibited by propranolol (10 µmol/L), but not by phentolamine (10 µmol/L) or atropine (10 µmol/L). The results suggest that noradrenaline release secondary to the activation of κ-bungarotoxin-sensitive nAChRs participates in LTP-like response induced by nicotine in the hippocampal CA1 region.