A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer's disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer's disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16-17), PSEN1 (exons 3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population.

Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family.

Alzheimer's disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation.

Assessment of ZnO and SiO2 nanoparticle permeability through and toxicity to the blood-brain barrier using Evans blue and TEM.

As increasing variants of nanoparticles (NPs) are being used in various products, it has become apparent that size alone can no longer adequately explain the variety of generated toxic profiles. Recent studies with NPs have suggested that various sizes of NPs could determine in vitro toxicity. In an attempt to address concerns regarding neurotoxicity of zinc oxide (ZnO) and silica (SiO2) NPs, these were examined after exposing them via oral, dermal, and intravenous administrations of NPs and their toxicological effects on the brain over a prescribed period of time were assessed. After 28 days of repeated oral administrations of ZnO or SiO2 independently, possibly due to damages to the blood brain barrier (BBB), neurotoxicity, were investigated by Evans blue technique. Next, in order to assess whether ZnO NPs could compromise the BBB, ZnO NPs were intravenously injected on day 0, 7, 14, 21 and 28 no further treatment was administered for 62 days. Deposition of SiO2 in brain from repeated dermal and oral administrations for 90 days were evaluated by transmission electron microscopy coupled with scanning energy-dispersive X-ray spectroscopy. Physiochemical profiles were principally determined on particle size at the beginning of the current toxicity investigations on ZnO and SiO2 NPs. The BBB was found to be intact after independent repeated oral administrations of ZnO or SiO2 NPs for 28 days, suggesting no significant damage. Neuronal death was also not observed after the intravenous administrations of ZnO NPs. After 90 days of repeated dermal and oral administration of SiO2 NPs, no deposition of NPs was observed in hippocampus, striatum, and cerebellum regions using transmission electron microscope analyses. These observations suggest that the BBB was not compromised and was able to block penetration of ZnO and SiO2 NPs, resulting in significant neurotoxic effects. Moreover, absence of SiO2 in three regions of brain after dermal and oral administrations for 90 days suggested that brain was protected from SiO2. No behavior change was observed in all studies, suggesting that 90 days may not be long enough to assess full neurotoxicity of NPs in vivo.