RhoC involved in the migration of neural stem/progenitor cells.

Alzheimer's disease (AD) is characterized by deposition of beta-amyloid peptides (Aß) and progressive loss of neurons. Neural stem/progenitor cells (NSPCs) can proliferate and produce immature neurons even in the brain of AD patients. However, Aß42 significantly decreased the expression of RhoC in NSPCs during the co-incubation (P < 0.01). Treating with RhoC siRNA prevented membrane from protrusion and led to a significant reduction in cell migration in responses to SDF-1. Compared with wild-type mice, the numbers of RhoC-immunoreactive cells in hippocampus and cortex were significantly down-regulated in APP/PS1 mice aged 9 months. The results suggest that Aß42 down-regulates the expression of RhoC in NSPCs in vitro and in vivo; down-regulated RhoC expression results in decreased migration of NSPCs.

A synergic role of caspase-6 and caspase-3 in Tau truncation at D421 induced by H2O 2.

Tau truncation is widely detected in Alzheimer's disease brain. Caspases activation is suggested to play a significant role in tau truncation at Aspartate 421 (D421) according to their ability to cleave recombinant tau in vitro. Ample evidence has shown that caspase-6 is involved in cognitive impairment and expressed in AD brain. Reactive oxygen species (ROS) can lead to caspase-6 activation and correlate with AD. Here, we transfected human embryonic kidney 293 (HEK 293) cells with Tau 441 plasmid and investigated the role of caspase-6 and caspase-3 in ROS-mediated tau truncation. Our data demonstrated that H2O2 induced oxidative stress and increased tau truncation. Caspase-6 and caspase-3 activity also increased in a dose-dependent manner in HEK 293/Tau cells during H2O2 insult. When cells were treated with an ROS inhibitor N-acetyl-L-cysteine, tau truncation was significantly suppressed. Compared with H2O2 (100 µM)/non-inhibitor group or single-inhibitor groups (z-VEID-fmk, caspase-6 inhibitor or z-DEVD-fmk, and caspase-3 inhibitor), tau truncation induced by H2O2 was effectively reduced in the combinative inhibitors group. Similar results were shown when cells were transfected with specific caspase-3 and caspase-6 siRNA. Inhibition of caspase-6 led to decline of caspase-3 activation. Taken together, our results suggest that the combination of caspase-6 and caspase-3 aggravates tau truncation at D421 induced by H2O2. Caspase-6 may play an important part in activating caspase-3. Further investigation of how the synergic role of caspase-6 and caspase-3 affects tau truncation may provide new visions for potential AD therapies.

Characterization of the APP/PS1 mouse model of Alzheimer's disease in senescence accelerated background.

The APP/PS1 mouse model of Alzheimer's disease (AD) exhibits remarkable elevation of ß-amyloid production associated with certain behavioral abnormalities, while the senescence accelerated mouse prone 8 (SAMP8) is characterized by early and age-related deterioration of learning and memory. In order to obtain an AD model that develops earlier pathological changes and cognitive impairment, we generated SAMP8-APP/PS1, a novel senescence accelerated APP/PS1 transgenic mouse model of AD. Standard histological staining and immunohistochemistry using an amyloid beta (Aß) antibody showed an age, genotype and strain-dependent progression of amyloid deposition and neuron loss in the cerebral cortex and hippocampus of SAMP8-APP/PS1 mice. Results from the cognitive behavioral tests revealed early deficits in learning and memory in SAMP8-APP/PS1 mice in the two way active avoidance and Morris water maze tests compared with C57-APP/PS1, SAMP8 wild-type and control mice. These results suggest that accelerated senescence exacerbates amyloid deposition and cognitive dysfunction in APP/PS1 mice and the senescence accelerated-APP/PS1 (SAMP8-APP/PS1) mouse model might be a valuable tool to study AD progression and to evaluate the effect of drugs on AD.

Effects of accelerated senescence on learning and memory, locomotion and anxiety-like behavior in APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a deficit in motor and spatial learning-memory and alteration of non-cognitive behavior. The generation of transgenic mice with presence of AD pathologies that cause learning and memory deficits has led to improved understanding of the behavioral and pathophysiological processes underlying AD. A novel APP/PS1 mouse model in the senescence accelerated mouse prone 8 (SAMP8) background--SAMP8 APP/PS1 was generated. To assess the behavioral and other AD-related changes in this SAMP8 APP/PS1 model, the present report covers a phenotypical analysis of this model for working memory, spatial memory, motor performance and anxiety-like behavior. SAMP8 APP/PS1 mice showed motor and spatial memory impairments, together with an increase of locomotor activity and lower anxiety-like behavior at 9months old. In contrast, C57 APP/PS1 and SAMP8 wild type mice were inconspicuous in all of these tasks and properties except C57 APP/PS1 mice which showed motor memory impairment in the shuttle box task at 9 months old. Standard senescence-associated beta-galactosidase (SA-beta-GAL) staining and amyloid beta (Aß) immunohistochemistry showed more severe pathological changes in the SAMP8 APP/PS1 mice. SAMP8 APP/PS1 mice exhibited earlier deficits in their non-cognitive and cognitive behaviors which are coincident in the AD patient and the results suggest that this new type of mice might be a better model for studying the age-related dementia of the Alzheimer type and for assessing the potential therapeutic agents for AD.

New nicotinic analogue ZY-1 enhances cognitive functions in a transgenic mice model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive loss of memory and cognitive function. One of the new approaches for treating AD is direct stimulation of nicotinic acetylcholine receptors (nAChRs) in the brain. α4ß2-nAChR agonists have shown promising potential in preclinical cognition models of AD. The present report describes the pharmacological properties of ZY-1, a new nicotinic analogue that activates α4ß2-nAChR. We describe in detail the binding profile and pharmacological effects of ZY-1 on transgenic AD mice. ZY-1 has high affinity to α4ß2-nAChR. In a Morris water maze test, ZY-1 significantly decreases the escape latency and increases both the times in the platform quadrant and the times of platform crossing of transgenic mice. ZY-1 enhances cognitive functions in transgenic mice models of AD. As a novel nicotinic analogue, ZY-1 deserves further study as a potential candidate against AD.

ß-amyloid42 induces desensitization of CXC chemokine receptor-4 via formyl peptide receptor in neural stem/progenitor cells.

The deposition of ß-amyloid (Aß) plaques and progressive loss of neurons are two main characteristics of Alzheimer's disease (AD). Supplement of neural stem/progenitor cells (NSPCs) is a promising strategy for repair of the neurodegenerative diseases. However, hostile microenvironment of neurodegenerative brain is harmful for the neuroregeneration. Aß(42) promoted the proliferation of NSPCs. Moreover, Aß(42) (10-1000 nM) promoted the migration of NSPCs in a dose-dependent manner. The attraction of NSPCs toward Aß(42) was significantly offset by 10 µM cyclosporin H, a potent and selective formyl peptide receptor antagonist. After incubation with Aß(42) for 9 d, the migration ability of NSPCs was significantly decreased (p<0.05). The expression of formyl peptide receptor (FPR) and CXC chemokine receptor-4 (CXCR4) were significantly decreased in NSPCs. The expression of G protein-coupled receptor kinase 2 (GRK2) was up-regulated on the membrane of NSPCs correspondingly. Our results suggested that Aß(42) decreases the migratory capacity of NSPCs by FPR heterologous desensitization after long time incubation, and GRK2 in NSPCs may be responsible for the damaged migratory capacity.