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.

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The present study was conducted to clarify a role of pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP type 1 receptor (PAC1R) in learning and memory function. We demonstrated long-term potentiation (LTP) in vivo in the dentate gyrus of PAC1R exon 2-deficient (PAC1R-/-) mice and heterozygous PACAP-deficient (PACAP+/-) mice using extracellular recording techniques. We used two paradigms of tetanic stimulation, suprathreshold and at threshold tetanus, which both induced LTP in vivo in PAC1R-/- and PACAP+/- mice. However, the population spike of 'at threshold' but not 'suprathreshold' LTP decreased significantly in PAC1R-/- and PACAP+/- mice. At threshold LTP of PACAP+/- mice was impaired greater than the one of PAC1R-/- mice. Thus, both PACAP and PAC1R could contribute to the establishment of LTP in a gene dosage-dependent manner, although PACAP rather than PAC1R might play a pivotal role in learning and memory function.

Perforant path long-term potentiation (LTP) in intact mouse hippocampal dentate gyrus increased the neuron-specific, growth-associated protein GAP-43 mRNA in hilar cells 3 days after tetanus, but surprisingly not in granule cells While it is now well established that long-term potentiation (LTP), a physiological model of the memory storage process, activates immediate early genes encoding transcription factors (1, 2), there is no evidence to our knowledge indicating what target genes are activated by these transcription factors. GAP-43, ¶ the presynaptically localized, growth-associated protein whose expression is up-regulated during axonal outgrowth in development and axonal regeneration (3), and whose phosphorylation is increased after LTP (4), is one likely candidate target gene (see also ref. 5). A previous study of chronic recording in intact freely moving rats 3 days after LTP induction revealed that perforant path LTP altered GAP-43 mRNA expression (6). To explore the hypothesis that the alteration in GAP-43 mRNA was related to altered transcriptional activity of the GAP-43 gene in hippocampal neurons after LTP, we first studied the effect of LTP in the intact mouse on the endogenous pattern of GAP-43 mRNA transcript levels with in situ hybridization. We then studied the effect of LTP on promoter activation in transgenic mice bearing a GAP-43 promoter-lacZ reporter construct. MATERIALS AND METHODSAnimals. Mouse strain C57BL͞6 was obtained from The Jackson Laboratory. Heterozygous GAP-43͞lacZ transgenic mouse line 252 bearing 6-kb 5Ј-flanking and 11-kb first intron sequence driving lacZ reporter gene was bred with C57BL͞6 mice, and homozygous transgenic mice were initially screened by genomic DNA Southern or dot hybridization. Constitutive expression of the transgene in hippocampus in GAP-43͞lacZ transgenic mouse line 252 has been described (7, 8). Thirty-five male homozygous transgenic mice (2 months old) were used in the electrophysiological and histochemical analysis.Electrophysiology. In vivo LTP in anesthetized mice was performed essentially as described previously (9). Potentiated responses were measured by percent baseline population spike amplitude. Mean potentiation of combined 1-, 2-, and 3-day LTP group animals was 255% Ϯ 40.1% (n ϭ 20; mean Ϯ SEM) over the 2-hr recording session and did not show any significant difference from that of wild-type C57BL͞6 mice (229.4% Ϯ 36.3%, P Ͼ 0.10). Mean response of the low-frequency control (LFC) animals during the 2-hr recording period was 101.1 Ϯ 5.5 (n ϭ 15). In the LTP experiment with DL-aminophosphonovalerate (APV; Sigma) ejection, 80 nl (1.6 nmol) of APV dissolved in 20 mM Tris⅐HCl (pH 8.0) was pressure-ejected from the recording micropipette into the dentate gyrus molecular layer, using procedures described earlier (10). APV was delivered 15 min prior to high-frequency tetanic stimulation. Equivalent volumes of 20 mM Tris vehicle were ejected into the same region of the hippocampus in control group animals. Potentiated responses in the molecul...