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Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice.

ABSTRACT: Calcium dysregulation is a key pathological event in Alzheimer's disease (AD). In studying approaches to mitigate this calcium overload, we identified the collapsin response mediator protein 2 (CRMP2), an axonal guidance protein that participates in synapse dynamics by interacting with and regulating activity of N-methyl-D-aspartate receptors (NMDARs). We further identified a 15 amino acid peptide from CRMP2 (designated CBD3, for calcium-binding domain 3), that reduced NMDAR-mediated Ca²⁺ influx in cultured neurons and post-synaptic NMDAR-mediated currents in cortical slices. Whether targeting CRMP2 could be therapeutically beneficial in AD is unknown. Here, using CBD3, we tested the utility of this approach. Employing the APP/PS1 mouse model of AD which demonstrates robust pathophysiology including A?1-42 deposition, altered tau levels, and diminished cognitive functions, we asked if overexpression of CBD3 could rescue these events. CBD3 was engineered into an adeno-associated vector and nasally delivered into APP/PS1 mice and then biochemical (immunohistochemistry, immunoblotting), cellular (TUNEL apoptosis assays), and behavioral (Morris water maze test) assessments were performed. APP/PS1 mice administered adeno-associated virus (AAV, serotype 2) harboring CBD3 demonstrated: (i) reduced levels of A?1-42 and phosphorylated-tau (a marker of AD progression), (ii) reduced apoptosis in the hippocampus, and (iii) reduced cognitive decline compared with APP/PS1 mice or APP/PS1 administered a control virus. These results provide an instructive example of utilizing a peptide-based approach to unravel protein-protein interactions that are necessary for AD pathology and demonstrate the therapeutic potential of CRMP2 as a novel protein player in AD.

SUBMITTER: Qi B

PROVIDER: S-EPMC7144060 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice.

Qi Baochang B Yang Yu Y Cheng Yingying Y Sun Di D Wang Xu X Khanna Rajesh R Ju Weina W

Molecular brain 20200409 1

Calcium dysregulation is a key pathological event in Alzheimer's disease (AD). In studying approaches to mitigate this calcium overload, we identified the collapsin response mediator protein 2 (CRMP2), an axonal guidance protein that participates in synapse dynamics by interacting with and regulating activity of N-methyl-D-aspartate receptors (NMDARs). We further identified a 15 amino acid peptide from CRMP2 (designated CBD3, for calcium-binding domain 3), that reduced NMDAR-mediated Ca<sup>2+</ ...[more]

PMID: 32272942

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Project description:Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both A? level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both A? levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg-1·d-1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate A? and sAPP? contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, TH? (1, 10, 20 ?g/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of A? clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained A? production as a suppressor against PERK/eIF2?-mediated BACE1 expression. Additionally, THA functioned as a GSK3? inhibitor with an IC50 of 1.32±0.85 ?g/mL, repressing Tau hyperphosphorylation. Similar effects on A? accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.

Dataset Information

Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice.

Publications

Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice.

Similar Datasets

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