Clinical characteristics and genotype-phenotype correlation analysis of familial Alzheimer's disease patients with pathogenic/likely pathogenic amyloid protein precursor mutations.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with aging, environmental, and genetic factors. Amyloid protein precursor (APP) is a known pathogenic gene for familial Alzheimer's disease (FAD), and now more than 70 APP mutations have been reported, but the genotype-phenotype correlation remains unclear. In this study, we collected clinical data from patients carrying APP mutations defined as pathogenic/likely pathogenic according to the American college of medical genetics and genomics (ACMG) guidelines. Then, we reanalyzed the clinical characteristics and identified genotype-phenotype correlations in APP mutations. Our results indicated that the clinical phenotypes of APP mutations are generally consistent with typical AD despite the fact that they show more non-demented symptoms and neurological symptoms. We also performed genotype-phenotype analysis according to the difference in APP processing caused by the mutations, and we found that there were indeed differences in onset age, behavioral and psychological disorders of dementia (BPSD) and myoclonus.

Genetics of progressive supranuclear palsy in a Chinese population.

BACKGROUND: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. METHODS: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. RESULTS: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10-3, p = 4.98 × 10-4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. CONCLUSIONS: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

Variants in the Niemann-pick type C genes are not associated with Alzheimer's disease: a large case-control study in the Chinese population.

Despite the similar clinical and pathological features between Niemann-Pick type C (NPC) disease and Alzheimer's disease (AD), few studies have investigated the role of NPC genes in AD. To elucidate the role of NPC genes in AD, we sequenced NPC1 and NPC2 in 1192 AD patients and 2412 controls. Variants were divided into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF≥0.01) based association analysis was conducted by PLINK 1.9. Gene-based aggregation testing of rare variants was performed by Sequence Kernel Association Test-Optimal (SKAT-O test), respectively. Age at onset (AAO) and mini-mental state examination (MMSE) association studies were also performed with PLINK 1.9. Six common variants were identified and exhibited no association with AD. Gene-based aggregation testing revealed that both NPC1 and NPC2 were not associated with AD risk. Additionally, AAO and MMSE association studies revealed that no common variants were linked with AD endophenotypes. Taken together, our study indicated that NPC1 and NPC2 may not be implicated in AD pathogenesis in the Chinese population.

Adhesive Materials Inspired by Barnacle Underwater Adhesion: Biological Principles and Biomimetic Designs.

Wet adhesion technology has potential applications in various fields, especially in the biomedical field, yet it has not been completely mastered by humans. Many aquatic organisms (e.g., mussels, sandcastle worms, and barnacles) have evolved into wet adhesion specialists with excellent underwater adhesion abilities, and mimicking their adhesion principles to engineer artificial adhesive materials offers an important avenue to address the wet adhesion issue. The crustacean barnacle secretes a proteinaceous adhesive called barnacle cement, with which they firmly attach their bodies to almost any substrate underwater. Owing to the unique chemical composition, structural property, and adhesion mechanism, barnacle cement has attracted widespread research interest as a novel model for designing biomimetic adhesive materials, with significant progress being made. To further boost the development of barnacle cement-inspired adhesive materials (BCIAMs), it is necessary to systematically summarize their design strategies and research advances. However, no relevant reviews have been published yet. In this context, we presented a systematic review for the first time. First, we introduced the underwater adhesion principles of natural barnacle cement, which lay the basis for the design of BCIAMs. Subsequently, we classified the BCIAMs into three major categories according to the different design strategies and summarized their research advances in great detail. Finally, we discussed the research challenge and future trends of this field. We believe that this review can not only improve our understanding of the molecular mechanism of barnacle underwater adhesion but also accelerate the development of barnacle-inspired wet adhesion technology.

Short Peptides Derived from a Block Copolymer-like Barnacle Cement Protein Self-Assembled into Diverse Supramolecular Structures.

Peptides capable of self-assembling into different supramolecular structures have potential applications in a variety of areas. The biomimetic molecular design offers an important avenue to discover novel self-assembling peptides. Despite this, a lot of biomimetic self-assembling peptides have been reported so far; to continually expand the scope of peptide self-assembly, it is necessary to find out more novel self-assembling peptides. Barnacle cp19k, a key underwater adhesive protein, shows special block copolymer-like characteristics and diversified self-assembly properties, providing an ideal template for biomimetic peptide design. In this study, inspired by Balanus albicostatus cp19k (Balcp19k), we rationally designed nine biomimetic peptides (P1-P9) and systematically studied their self-assembly behaviors for the first time. Combining microscale morphology observations and secondary structure analyses, we found that multiple biomimetic peptides derived from the central region and the C-terminus of Balcp19k form distinct supramolecular structures via different self-assembly mechanisms under acidic conditions. Specifically, P9 self-assembles into typical amyloid fibers. P7, which resembles ionic self-complementary peptides by containing nonstrictly alternating hydrophobic and charged amino acids, self-assembles into uniform, discrete nanofibers. P6 with amphipathic features forms twisted nanoribbons. Most interestingly, P4 self-assembles to form helical nanofibers and novel ring-shaped microstructures, showing unique self-assembly behaviors. Apart from their self-assembly properties, these peptides showed good cytocompatibility and demonstrated promising applications in biomedical areas. Our results expanded the repertoire of self-assembling peptides and provided new insights into the structure-function relationship of barnacle cp19k.