Amyloid b-protein (Ab) and a-synuclein (aS) are the primary components of amyloid plaques and Lewy bodies (LBs), respectively. Aggregations of Ab and aS are considered to be a critical step during neurodegeneration associated with Alzheimer's disease (AD) and Lewy body diseases (LBD), respectively. The AD is characterized by the accumulation of Ab plaques and neurofibrillary tangles. Interestingly, up to 50% of AD cases exhibit significant LB pathology in addition to plaques and tangles (Hamilton 2000). Likewise, patients with dementia with LBs (DLB) frequently exhibit AD pathology, particularly senile plaques (Armstrong et al. 1997).Recent studies suggest that accumulations of oligomers might be the neurotoxic species, rather than fibrils. The progressive accumulation of Ab oligomers has been identified as a central toxic event during AD that leads to synaptic dysfunction (Ono and Yamada 2011), whereas the formation of aS oligomers that disrupt membrane and mitochondrial activity has been linked to LBD (Kim et al. 2009).It was previously shown that Ab enhances aS accumulation and neuronal deficits using transgenic mice with neuronal expression of Ab and aS (Masliah et al. 2001). Nuclear magnetic resonance study showed that Ab and aS might interact directly at a few sites (Mandal et al. 2006). A recent in vitro study reported that Ab and aS might interact directly to form hybrid pore-like oligomers that contribute to neurodegeneration (Tsigelny et al. 2008). These studies suggest that interactions between Ab and aS are involved in the pathogenesis of AD and LBD, but the seeding effects of their aggregates on aggregation pathways have not been elucidated. Thus, we determined whether fibrils or crosslinked oligomers of Ab40, Ab42, and aS have cross-seeding effects on each other's aggregation pathways in vitro. Abbreviations used: Ab, amyloid b-protein; AD, Alzheimer's disease; APP, amyloid precursor protein; APS, ammonium persulfate; aS, a-synuclein; DLB, dementia with Lewy bodies; EM, electron microscopy; fAb, Ab fibrils; faS, aS fibrils; LBD, Lewy body diseases; LBs, Lewy bodies; NAC, non-amyloid component; oligo, cross-linked oligomers; PD, Parkinson's disease; PICUP, photo-induced cross-linking of unmodified proteins; Ru(bpy), tris(2,2¢-bipyridyl)dichlororuthenium(II) hexahydrate; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; ThS, Thioflavin S; ThT, Thioflavin T. However, the seeding effects of their aggregates on their aggregation pathways are not completely clear. To investigate the cross-seeding effects of Ab and aS, we examined how sonicated fibrils or cross-linked oligomers of Ab40, Ab42, and aS affected their aggregation pathways using thioflavin T(S) assay and electron microscopy. Fibrils and oligomers of Ab40, Ab42, and aS acted as seeds, and affected the aggregation pathways within and among species. The seeding effects of aS fibrils were higher than those of Ab40 and Ab42 fibrils in the Ab40 and Ab42 aggregation pathways, respectively. We showed that Ab and aS acted as seeds an...

Background: Epidemiological evidence suggests that consumption of phenolic compounds reduce the incidence of Alzheimer disease (AD). Results: Myricetin and rosmarinic acid reduced cellular and synaptic toxicities by inhibition of amyloid ␤-protein (A␤) oligomerization. Myricetin promoted NMR changes of A␤. Conclusion: Phenolic compounds are worthy therapeutic candidates for AD. Significance: Phenolic compounds blocked early assembly processes of A␤ through differently binding.

Although metal intoxication after arthroplasty causes various symptoms, polyneuropathy has never been the focus of clinical investigation. We report the case of a 56‐year‐old woman with metal neuropathy. She had metallosis after hip arthroplasty with a cobalt–chromium alloy prosthesis. She developed progressive sensory disturbance, hearing loss, and hypothyroidism. Sural nerve biopsy indicated axonopathy. After exchange arthroplasty, blood levels of cobalt and chromium decreased, and her symptoms improved. Cobalt or chromium can cause axonopathy. Muscle Nerve, 2010

Lewy bodies comprised of aggregates of α-synuclein (αS) in the brain are the main histopathological features of Lewy body diseases (LBD) such as Parkinson's disease and dementia with Lewy bodies. Mutations such as E46K, A30P and A53T in the αS gene cause autosomal dominant LBD in a number of kindreds. Although these mutations accelerate fibril formation, their precise effects at early stages of the αS aggregation process remain unknown. To answer this question, we examined the aggregation including monomer conformational dynamics and oligomerization of the E46K, A30P, A53T and A30P/A53T mutations and wild type (WT) using thioflavin S assay, circular dichroism spectroscopy, photo-induced cross-linking of unmodified proteins, electron microscopy, and atomic force microscopy. Relative to WT αS, E46K αS accelerated the kinetics of the secondary structure change and oligomerization, whereas A30P αS decelerated them. These effects were reflected in changes in average oligomer size.The mutant oligomers of E46K αS functioned as fibril seeds significantly more efficiently than those of WT αS, whereas the mutant oligomers of A30P αS were less efficient. Our results that mutations of familial LBD had opposite effects at early stages of αS assembly may provide new insight into the molecular mechanisms of LBD.

Lewy bodies, mainly composed of a-synuclein (aS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited aS fibrillation and destabilized preformed aS fibrils. Cumulative evidence suggests that loworder aS oligomers are neurotoxic and critical species in the pathogenesis of a-synucleinopathies. To develop disease modifying therapies for a-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on aS oligomerization. Using methods such as photoinduced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited aS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of aS, whereas direct binding of RA to monomeric aS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated aS synaptic toxicity by inhibition of aS oligomerization. These results suggest that Myr and RA prevent the aS aggregation process, reducing the neurotoxicity of aS oligomers.