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Intravenously Injected Amyloid-? Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral ?-Amyloidosis in A?PP/PS1 Transgenic Mice Model of Alzheimer's Disease.

ABSTRACT: Cerebral ?-amyloidosis, an accumulation in the patient's brain of aggregated amyloid-? (A?) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer's disease (AD). Earlier, we found that exogenously administrated synthetic A? with isomerized Asp7 (isoD7-A?) induces A? fibrillar aggregation in the transgenic mice model of AD. IsoD7-A? molecules have been implied to act as seeds enforcing endogenous A? to undergo pathological aggregation through zinc-mediated interactions. On the basis of our findings on zinc-induced oligomerization of the metal-binding domain of various A? species, we hypothesize that upon phosphorylation of Ser8, isoD7-A? loses its ability to form zinc-bound oligomeric seeds. In this work, we found that (i) in vitro isoD7-A? with phosphorylated Ser8 (isoD7-pS8-A?) is less prone to spontaneous and zinc-induced aggregation in comparison with isoD7-A? and intact A? as shown by thioflavin T fluorimetry and dynamic light scattering data, and (ii) intravenous injections of isoD7-pS8-A? significantly slow down the progression of institutional ?-amyloidosis in A?PP/PS1 transgenic mice as shown by the reduction of the congophilic amyloid plaques' number in the hippocampus. The results support the role of the zinc-mediated oligomerization of A? species in the modulation of cerebral ?-amyloidosis and demonstrate that isoD7-pS8-A? can serve as a potential molecular tool to block the aggregation of endogenous A? in AD.

SUBMITTER: Kozin SA

PROVIDER: S-EPMC6119768 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer's Disease.

Kozin Sergey A SA Barykin Evgeny P EP Telegin Georgy B GB Chernov Alexander S AS Adzhubei Alexei A AA Radko Sergey P SP Mitkevich Vladimir A VA Makarov Alexander A AA

Frontiers in neuroscience 20180823

Cerebral β-amyloidosis, an accumulation in the patient's brain of aggregated amyloid-β (Aβ) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer's disease (AD). Earlier, we found that exogenously administrated synthetic Aβ with isomerized Asp7 (isoD7-Aβ) induces Aβ fibrillar aggregation in the transgenic mice model of AD. IsoD7-Aβ molecules have been implied to act as seeds enforcing endogenous Aβ to undergo pathological aggregation through zinc-mediated ...[more]

PMID: 30210271

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Project description:IntroductionCell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined.MethodsIn this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an A?PP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid ?-peptides (A?) deposition, and microglial function of the mice were investigated.ResultsWe found that transplantation of HUMSC-NCs into A?PP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced A? deposition in the mice. The beneficial effects were associated with "alternatively activated" microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?), was significantly reduced. Moreover, the expression of A?-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs.ConclusionsHUMSC-NC transplantation decreased A? deposition and improved memory in A?PP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.

Project description:BackgroundAlzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.MethodsAPP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.ResultsIn APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.ConclusionsApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

Dataset Information

Intravenously Injected Amyloid-? Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral ?-Amyloidosis in A?PP/PS1 Transgenic Mice Model of Alzheimer's Disease.

Publications

Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer's Disease.

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