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C₃N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer's disease.

ABSTRACT: Despite the accumulating evidence linking the development of Alzheimer's disease (AD) to the aggregation of Aβ peptides and the emergence of Aβ oligomers, the FDA has approved very few anti-aggregation-based therapies over the past several decades. Here, we report the discovery of an Aβ peptide aggregation inhibitor: an ultra-small nanodot called C₃N. C₃N nanodots alleviate aggregation-induced neuron cytotoxicity, rescue neuronal death, and prevent neurite damage in vitro. Importantly, they reduce the global cerebral Aβ peptides levels, particularly in fibrillar amyloid plaques, and restore synaptic loss in AD mice. Consequently, these C₃N nanodots significantly ameliorate behavioral deficits of APP/PS1 double transgenic male AD mice. Moreover, analysis of critical tissues (e.g., heart, liver, spleen, lung, and kidney) display no obvious pathological damage, suggesting C₃N nanodots are biologically safe. Finally, molecular dynamics simulations also reveal the inhibitory mechanisms of C₃N nanodots in Aβ peptides aggregation and its potential application against AD.

SUBMITTER: Yin X

PROVIDER: S-EPMC10504243 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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C3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer's disease.

Yin Xiuhua X Zhou Hong H Zhang Mengling M Su Juan J Wang Xiao X Li Sijie S Yang Zaixing Z Kang Zhenhui Z Zhou Ruhong R

Nature communications 20230915 1

Despite the accumulating evidence linking the development of Alzheimer's disease (AD) to the aggregation of Aβ peptides and the emergence of Aβ oligomers, the FDA has approved very few anti-aggregation-based therapies over the past several decades. Here, we report the discovery of an Aβ peptide aggregation inhibitor: an ultra-small nanodot called C3N. C3N nanodots alleviate aggregation-induced neuron cytotoxicity, rescue neuronal death, and prevent neurite damage in vitro. ...[more]

PMID: 37714837

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Project description:SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, and frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD, and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI, and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin-T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8 ± 2.4%), MCI (32.8 ± 5.4%), and preclinical AD (28.3 ± 6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6 ± 2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin-T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.

Project description:SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8±2.4%), MCI (32.8±5.4%) and preclinical AD (28.3±6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6±2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.

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C₃N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer's disease.

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C<sub>3</sub>N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer's disease.

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