Dataset Information

Targeting Apolipoprotein E/Amyloid ? Binding by Peptoid CPO_A?17-21?P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline.

ABSTRACT: Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-? (A?) peptides at residues 12-28 of A? and this binding modulates A? accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/A? interaction with A?12-28?P reduced A? and tau-related pathology, leading to cognitive improvements in treated AD mice. Recently, we have designed a small peptoid library derived from the A?12-28?P sequence to screen for new apoE/A? binding inhibitors with higher efficacy and safety. Peptoids are better drug candidates than peptides due to their inherently more favorable pharmacokinetic properties. One of the lead peptoid compounds, CPO_A?17-21?P, diminished the apoE/A? interaction and attenuated the apoE4 pro-fibrillogenic effects on A? aggregation in vitro as well as apoE4 potentiation of A? cytotoxicity. CPO_A?17-21?P reduced A?-related pathology coupled with cognitive improvements in an AD APP/PS1 transgenic mouse model. Our study suggests the non-toxic, non-fibrillogenic peptoid CPO_A?17-21?P has significant promise as a new AD therapeutic agent which targets the A? related apoE pathway, with improved efficacy and pharmacokinetic properties.

SUBMITTER: Liu S

PROVIDER: S-EPMC5556019 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Targeting Apolipoprotein E/Amyloid β Binding by Peptoid CPO_Aβ17-21 P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline.

Liu Shan S Park Shinae S Allington Grant G Prelli Frances F Sun Yanjie Y Martá-Ariza Mitchell M Scholtzova Henrieta H Biswas Goutam G Brown Bernard B Verghese Philip B PB Mehta Pankaj D PD Kwon Yong-Uk YU Wisniewski Thomas T

Scientific reports 20170814 1

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-β (Aβ) peptides at residues 12-28 of Aβ and this binding modulates Aβ accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aβ interaction with Aβ12-28 P reduced Aβ and tau-related pathology, leading to cognitive imp ...[more]

PMID: 28808293

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Project description:BackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.MethodologyAccumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1-/- mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04+ fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory.ResultsDisease progression in 5xFAD;Cx3cr1-/- mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1-/- mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1-/- mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1-/- mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA.ConclusionsCx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1-/- mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.

Project description:BackgroundCortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly.MethodsThe discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables.ResultsIn bivariate analyses, older age (r = -0.11, p = 0.029), male sex (t = -3.00, p = 0.003), larger intracranial volume (r = -0.17, p < 0.001), carrying an APOEe4 allele (t = -2.71, p = 0.007), larger white matter lesion volume (r = -0.16, p = 0.002), lower cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio (t = -4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = -0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = -0.15, p = 0.003), and neurofilament light (NfL; r = -0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aβ42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aβ42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume.ConclusionsOur results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.

Dataset Information

Targeting Apolipoprotein E/Amyloid ? Binding by Peptoid CPO_A?17-21?P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline.

Publications

Targeting Apolipoprotein E/Amyloid β Binding by Peptoid CPO_Aβ17-21 P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline.

Similar Datasets

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