Although amyloid ␤ (A␤) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features of AD remains unclear. To address the latter, we generated APP transgenic mice expressing the E693⌬ mutation, which causes AD by enhanced A␤ oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal A␤ oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that A␤ oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are a useful model of A␤ oligomer-induced pathology in the absence of amyloid plaques.

The present study was conducted to clarify the role of nicotinic ACh receptors (nAChRs) on long-term potentiation (LTP) in vivo in the intact mouse dentate gyrus using extracellular recording techniques. Intraperitoneal application of nicotine at a dose of 3.0 mg/kg but not 0.03 or 0.3 mg/kg produced a gradually developing, long-lasting increase for 120 min similar to tetanic LTP. Nicotine at a dose of 9. 0 mg/kg caused a temporary increase followed by depression. The long-lasting potentiation induced by nicotine at 3.0 mg/kg, which was named nicotinic long-term potentiation (LTPn), and tetanic LTP were significantly suppressed by pretreatment with mecamylamine (0.5 mg/kg i.p.), a nonselective nicotinic antagonist, but not affected by postapplication of mecamylamine. Interestingly, choline, a selective alpha7 nAChR agonist, at 3.0-90 mg/kg, induced the long-lasting potentiation similar to LTPn in a dose-dependent manner in vivo in the intact mouse dentate gyrus. The long-lasting potentiation induced by choline (30 mg/kg i.p.) was additionally increased by postapplication of nicotine (3.0 mg/kg i.p.) or tetanic stimulation. The present study revealed that systemic application of nicotine or choline induced the long-lasting potentiation in vivo in the intact mouse dentate gyrus, suggesting that alpha7 nAChRs may contribute to the induction of LTP by nicotine, and supporting in vivo animal studies that nicotine improves learning and memory performance.

Background and purpose: Neurons with atrophic neurites may remain alive and therefore may have the potential to regenerate even when neuronal death has occurred in some parts of the brain. This study aimed to explore effects of drugs that can facilitate the regeneration of neurites and the reconstruction of synapses even in severely damaged neurons. Experimental approach: We investigated the effects of extracts of Astragalus mongholicus on the cognitive defect in mice caused by injection with the amyloid peptide . We also examined the effect of the extract on the regeneration of neurites and the reconstruction of synapses in cultured neurons damaged by . Key results: A. mongholicus extract (1 g kg À1 day À1 for 15 days, p.o.) reversed Ab(25-35)-induced memory loss and prevented the loss of axons and synapses in the cerebral cortex and hippocampus in mice. Treatment with Ab(25-35) (10 mM) induced axonal atrophy and synaptic loss in cultured rat cortical neurons. Subsequent treatment with A. mongholicus extract (100 mg/ ml) resulted in significant axonal regeneration, reconstruction of neuronal synapses, and prevention of Ab(25-35)-induced neuronal death. Similar extracts of A. membranaceus had no effect on axonal atrophy, synaptic loss, or neuronal death. The major known components of the extracts (astragalosides I, II, and IV) reduced neurodegeneration, but the activity of the extracts did not correlate with their content of these three astragalosides. Conclusion and implications: A. mongholicus is an important candidate for the treatment of memory disorders and the main active constituents may not be the known astragalosides. Keywords: dementia; axon; synapse; neuronal death; Astragali radix; Astragalus mongholicus; astragalosides; morris water maze; Abbreviations: NF-H, neurofilament-H; NGF, nerve growth factor IntroductionIn addition to the death of neurons, atrophy of neurites and loss of synapses are the major causes of dysfunctions of the brain including Alzheimer's (DeKosky and Scheff, 1990;Terry et al., 1991;Dickson and Vickers, 2001), Parkinson's, Huntington and Creutzfeldt-Jakob diseases (Jackson et al., 1995;Liberski and Budka, 1999;Mattila et al., 1999). Neurons with atrophic neurites may remain alive and therefore may have the potential to regenerate even when neuronal death has occurred in some parts of the brain. We have hypothesized that reconstructing neuronal networks in the injured brain is essential for the recovery of brain function . To reconstruct neuronal networks, neurites must be regenerated and synapses must be reconstructed. In the current studies, we explored the in vitro and in vivo effects of drugs that can facilitate the regeneration of neurites and the reconstruction of synapses even in severely damaged neurons.Astragali radix (the root of Astragalus mongholicus Bunge or A. membranaceus Bunge) is used mainly as a tonic agent in traditional Chinese and Japanese Kampo medicine. A few reports show that Astragali Radix extract or its components can affect brain function. For example...

The KICG can identify reversible liver injury in septic shock, suggesting good prognosis. Either failure to increase the KICG within 120 hrs or an extremely low KICG is a poor prognostic sign.

No abstract