37 research outputs found
Spatial navigation deficits in early Alzheimer's disease: the role of biomarkers and APOE genotype
No full textBACKGROUND: Spatial navigation deficits are early symptoms of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation.METHODS: 107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants.RESULTS: AD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance.CONCLUSIONS: These findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.</p
Data_Sheet_1_Neurons Induced From Fibroblasts of c9ALS/FTD Patients Reproduce the Pathology Seen in the Central Nervous System.pdf
No full textAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the c9orf72 gene is the most common genetic cause of ALS/FTD. We present a cellular model of c9ALS/FTD where induced neurons (iNeurons) are generated within 2 weeks by direct conversion of patients‘ dermal fibroblasts through down-regulation of polypyrimidine-tract-binding protein 1 (PTB1). While sense (S) and anti-sense (AS) intranuclear RNA foci were observed in both fibroblasts and iNeurons, the accumulation of (S) and (AS) repeat-associated non-ATG translation (RANT) products were detected only in iNeurons. Importantly, anti-sense oligonucleotides (ASOs) against the (S) repeat transcript lead to decreased (S) RNA foci staining and a reduction of the corresponding RANT products without affecting its (AS) counterparts. ASOs treatment also rescued the cell viability upon stressful stimulus. The results indicate that iNeurons is an advantageous model that not only recapitulates c9ALS/FTD hallmark features but can also help uncover promising therapeutics.</p
KLOTHO-VS heterozygosity, α-klotho protein levels and cognitive performance in Alzheimer’s disease
No full textAbstract Background KLOTHO-VS (KL-VS) heterozygosity, a variant of the KLOTHO gene, and its encoded protein, α-Klotho, are associated with brain health and show neuroprotective potential against Alzheimer’s disease (AD). We aimed to assess whether KL-VS heterozygosity, cerebrospinal fluid (CSF) and serum soluble α-Klotho (sαKl) levels, would be associated with a lower likelihood of AD and better performance on memory and other cognitive domains in individuals with AD dementia, amnestic mild cognitive impairment (aMCI) due to AD, and cognitively unimpaired controls. Methods In this cross-sectional study, we analyzed two partially overlapping subsamples derived from 296 participants from the Czech Brain Aging Study. The first subsample included 196 participants with KL-VS haplotype data: 71 with AD dementia, 84 with aMCI due to AD, and 41 cognitively unimpaired controls. The second subsample included 147 participants with CSF and/or serum sαKl measurements, including 58 with AD dementia, 59 with aMCI due to AD, and 30 cognitively unimpaired controls. Diagnoses of aMCI and AD dementia were confirmed by positive CSF biomarkers and/or amyloid PET imaging. Logistic regression assessed how KL-VS heterozygosity influenced the odds of aMCI or dementia due to AD. Linear regression investigated associations between cognitive performance and either KL-VS heterozygosity or CSF/serum sαKl levels. Analysis of variance and analysis of covariance with post-hoc tests were used to compare sαKl levels across study groups. Results KL-VS heterozygosity carriers showed a consistent trend towards lower odds of being classified with aMCI and dementia due to AD, with similar patterns in both Apolipoprotein E ε4 (APOE ε4) allele carriers and non-carriers, although none of the associations reached statistical significance despite moderate (rather than small) effect sizes. Among individuals with aMCI due to AD, KL-VS heterozygotes displayed better memory performance (β = 0.61, p = .008), particularly those who also carried the APOE ε4 allele (β = 0.64, p = .042). Results with other cognitive domains were non-significant. No significant differences in sαKl levels were found between study groups, and soluble α-Klotho levels did not associate with memory performance. Conclusions KL-VS heterozygosity may be linked to lower likelihood of classification as aMCI or dementia due to AD, and its association with memory might be specific to the aMCI stage of AD and modulated by APOE ε4 status
Chitinase mRNA Levels Determined by QPCR in Crab-Eating Monkey (Macaca fascicularis) Tissues: Species-Specific Expression of Acidic Mammalian Chitinase and Chitotriosidase
No full textMice and humans express two active chitinases: acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Both chitinases are thought to play important roles in specific pathophysiological conditions. The crab-eating monkey (Macaca fascicularis) is one of the most frequently used nonhuman primate models in basic and applied biomedical research. Here, we performed gene expression analysis of two chitinases in normal crab-eating monkey tissues by way of quantitative real-time polymerase chain reaction (qPCR) using a single standard DNA molecule. Levels of AMCase and CHIT1 messenger RNAs (mRNAs) were highest in the stomach and the lung, respectively, when compared to other tissues. Comparative gene expression analysis of mouse, monkey, and human using monkey–mouse–human hybrid standard DNA showed that the AMCase mRNA levels were exceptionally high in mouse and monkey stomachs while very low in the human stomach. As for the CHIT1 mRNA, we detected higher levels in the monkey lung when compared with those of mouse and human. The differences of mRNA expression between the species in the stomach tissues were basically reflecting the levels of the chitinolytic activities. These results indicate that gene expression of AMCase and CHIT1 differs between mammalian species and requiring special attention in handling data in chitinase-related studies in particular organisms
Acidic Chitinase-Chitin Complex Is Dissociated in a Competitive Manner by Acetic Acid: Purification of Natural Enzyme for Supplementation Purposes
No full textAcidic chitinase (Chia) has been implicated in asthma, allergic inflammations, and food processing. We have purified Chia enzymes with striking acid stability and protease resistance from chicken and pig stomach tissues using a chitin column and 8 M urea (urea-Chia). Here, we report that acetic acid is a suitable agent for native Chia purification from the stomach tissues using a chitin column (acetic acid-Chia). Chia protein can be eluted from a chitin column using 0.1 M acetic acid (pH 2.8), but not by using Gly-HCl (pH 2.5) or sodium acetate (pH 4.0 or 5.5). The melting temperatures of Chia are not affected substantially in the elution buffers, as assessed by differential scanning fluorimetry. Interestingly, acetic acid appears to be more effective for Chia-chitin dissociation than do other organic acids with similar structures. We propose a novel concept of this dissociation based on competitive interaction between chitin and acetic acid rather than on acid denaturation. Acetic acid-Chia also showed similar chitinolytic activity to urea-Chia, indicating that Chia is extremely stable against acid, proteases, and denaturing agents. Both acetic acid- and urea-Chia seem to have good potential for supplementation or compensatory purposes in agriculture or even biomedicine
P1‐529: IMPACT OF BDNF AND APOE POLYMORPHISM ON COGNITIVE PERFORMANCE IN PATIENTS AT INCREASED RISK OF DEVELOPING ALZHEIMER'S DISEASE
No full textCrab-Eating Monkey Acidic Chitinase (CHIA) Efficiently Degrades Chitin and Chitosan under Acidic and High-Temperature Conditions
No full textChitooligosaccharides, the degradation products of chitin and chitosan, possess anti-bacterial, anti-tumor, and anti-inflammatory activities. The enzymatic production of chitooligosaccharides may increase the interest in their potential biomedical or agricultural usability in terms of the safety and simplicity of the manufacturing process. Crab-eating monkey acidic chitinase (CHIA) is an enzyme with robust activity in various environments. Here, we report the efficient degradation of chitin and chitosan by monkey CHIA under acidic and high-temperature conditions. Monkey CHIA hydrolyzed α-chitin at 50 °C, producing N-acetyl-d-glucosamine (GlcNAc) dimers more efficiently than at 37 °C. Moreover, the degradation rate increased with a longer incubation time (up to 72 h) without the inactivation of the enzyme. Five substrates (α-chitin, colloidal chitin, P-chitin, block-type, and random-type chitosan substrates) were exposed to monkey CHIS at pH 2.0 or pH 5.0 at 50 °C. P-chitin and random-type chitosan appeared to be the best sources of GlcNAc dimers and broad-scale chitooligosaccharides, respectively. In addition, the pattern of the products from the block-type chitosan was different between pH conditions (pH 2.0 and pH 5.0). Thus, monkey CHIA can degrade chitin and chitosan efficiently without inactivation under high-temperature or low pH conditions. Our results show that certain chitooligosaccharides are enriched by using different substrates under different conditions. Therefore, the reaction conditions can be adjusted to obtain desired oligomers. Crab-eating monkey CHIA can potentially become an efficient tool in producing chitooligosaccharide sets for agricultural and biomedical purposes
Spatial navigation and verbal memory are influenced by the combined effects of APOE and BDNF Val66Met polymorphisms in mild cognitive impairment
No full textP1‐182: The Effect of APOE E4 on Episodic Memory in Patients with Amnestic Mild Cognitive Impairment
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