Dataset Information

Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease.

ABSTRACT:

Background and purpose

In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy.

Experimental approach

We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of β-amyloid (Aβ) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aβ lowering and anti-Aβ oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features.

Conclusion and implications

Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aβ lowering and anti-aggregation dual activities for AD.

SUBMITTER: Wang J

PROVIDER: S-EPMC3966818 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease.

Wang Jun J Land David D Ono Kenjiro K Galvez Jorge J Zhao Wei W Vempati Prashant P Steele John W JW Cheng Alice A Yamada Masahito M Levine Samara S Mazzola Paolo P Pasinetti Giulio M GM

PloS one 20140326 3

<h4>Background and purpose</h4>In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation ...[more]

PMID: 24671215

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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.

Dataset Information

Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease.

Background and purpose

Experimental approach

Conclusion and implications

Publications

Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease.

Similar Datasets

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