The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.

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.

We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[ Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.

Aggregation of physiologically produced soluble amyloid ␤ protein (A␤) to insoluble, neurotoxic fibrils is a crucial step in the pathogenesis of Alzheimer's disease. Aggregation studies with synthetic A␤1-40 peptide by the thioflavin T fluorescence assay and electron microscopy and cytotoxicity assays using rat pheochromocytoma PC12 cells showed that an antibiotic, rifampicin, and its derivatives, which possess a naphthohydroquinone or naphthoquinone structure, inhibited A␤1-40 aggregation and neurotoxicity in a concentration-dependent manner. Hydroquinone, p-benzoquinone, and 1,4-dihydroxynaphthalene, which represent partial structures of the aromatic chromophore of rifampicin derivatives, also inhibited A␤1-40 aggregation and neurotoxicity at comparable molar concentrations to rifampicin. Electron spin resonance spectrometric analysis revealed that the inhibitory activities of those agents correlated with their radical-scavenging ability on hydroxyl free radical, which was shown to be generated in cell-free incubation of A␤1-40 peptide. These results suggest that at least one mechanism of rifampicin-mediated inhibition of A␤ aggregation and neurotoxicity involves scavenging of free radicals and that rifampicin and/or appropriate hydroxyl radical scavengers may have therapeutic potential for Alzheimer's disease.Amyloid ␤ protein (A␤), 1 a 39 -43 amino acid peptide, is a primary component of the amyloid that is deposited in the brains of patients with Alzheimer's disease (AD). A␤ is physiologically produced as a soluble form by enzymatic cleavage of the larger precursor, termed amyloid precursor protein (1-3). Soluble A␤ is not toxic and its physiological function is not known; however, it has been shown that aggregation of A␤ to insoluble fibrils causes neurotoxic change of the peptide (4 -6). Therefore, inhibition of this process would seem to be an effective therapeutic strategy for AD.The mechanisms of A␤ aggregation and neurotoxicity are not completely known. Recently, it was suggested that free radical generation may be involved in the processes of A␤ aggregation and/or neurotoxicity (7-9). Those hypotheses imply that appropriate radical scavengers could inhibit A␤ aggregation and/or neurotoxicity.It was previously reported that non-demented elderly leprosy patients showed an unusual absence of senile plaques in their brains compared with age-matched controls (10). Although that finding itself is still a matter of controversy (11), we surmised that some drug being used for leprosy might be preventing A␤ aggregation, resulting in the absence of amyloid deposition. Thus, we tested two well known anti-leprosy drugs, dapsone and rifampicin, and found that rifampicin inhibited A␤1-40 aggregation and neurotoxicity in vitro (12). Rifampicin is a semisynthetic derivative of the rifamycins, a class of antibiotics that are fermentation products of Nocardia mediterranei (for a review, see Ref. 13). The common structure of rifamycins is a naphthohydroquinone or naphthoquinone chromophore spanned by an aliphatic ansa c...

Intraneuronal accumulation of amyloid β (Aβ) is an early pathological change in Alzheimer's disease. Previously, we showed that the E693Δ mutation (referred to as the "Osaka" mutation) of amyloid precursor protein (APP) caused intracellular accumulation of Aβ oligomers and apoptosis in transfected COS-7 cells. We also showed that transgenic mice expressing APP(E693Δ) (APP(OSK) ) displayed both an age-dependent accumulation of intraneuronal Aβ oligomers from 8 months of age and apparent neuronal loss in the hippocampus at 24 months of age. These findings indicate that intraneuronal Aβ oligomers cause cell death, but the mechanism of this process remains unclear. Accordingly, here we investigated the subcellular localization and toxicity of intraneuronal Aβ oligomers in APP(OSK) -transgenic mice. We found Aβ oligomer accumulation in the endoplasmic reticulum (ER), endosomes/lysosomes, and mitochondria in hippocampal neurons of 22-month-old mice. We also detected up-regulation of Grp78 and HRD1 (an E3 ubiquitin ligase), leakage of cathepsin D from endosomes/lysosomes into cytoplasm, cytochrome c release from mitochondria, and activation of caspase-3 in the hippocampi of 18-month-old mice. Collectively, our findings suggest that intraneuronal Aβ oligomers cause cell death by inducing ER stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. © 2011 Wiley-Liss, Inc.