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. 2017 May;9(5):703-715.
doi: 10.15252/emmm.201606666.

An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice

Yu-Sung Cheng  1 , Zih-Ten Chen  2 , Tai-Yan Liao  2 , Chen Lin  2 , Howard C-H Shen  2 , Ya-Han Wang  2   3 , Chi-Wei Chang  4 , Ren-Shyan Liu  4   5 , Rita P-Y Chen  6   3 , Pang-Hsien Tu  7
Affiliations

An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice

Yu-Sung Cheng et al. EMBO Mol Med. 2017 May.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Aβ(25-35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Aβ(25-35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases.

Keywords: Alzheimer disease; Aβ; peptide therapy; polyarginine; polyethylenimine.

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Figures

Figure 1
Figure 1. The inhibition model of R8‐Aβ(25–35) and the dose‐dependent effect of R8‐Aβ(25–35) on inhibition of Aβ40 fibrillization
Aβ40 was mixed with R8‐Aβ(25–35) in different mixing ratios (Aβ40:R8‐Aβ(25–35) = 1:0.1, 1:0.2, 1:1). The Aβ40 concentration is 30 μM. The peptides were dissolved in 20 mM sodium phosphate buffer with 150 mM KCl (pH 7) and incubated at 25°C.
  1. A

    Proposed working mechanism.

  2. B–E

    CD spectra of Aβ40 alone (B) and three Aβ40/R8‐Aβ(25–35) mixtures (C, 1:0.1; D, 1:0.2; E, 1:1) were recorded at the indicated incubation times.

  3. F–I

    TEM images of the samples in (B), (C), (D), and (E) taken at the indicated incubation times are shown in (F), (G), (H), and (I), respectively.

Figure 2
Figure 2. Cell viability measurement by MTT assays

  1. Neuro2a cells treated with DMSO (control), Aβ40, R8‐Aβ(25–35), or DR8‐Aβ(25–35).

  2. Neuro2a cells treated with DMSO (control), Aβ40, and Aβ40 with equal molar R8‐Aβ(25–35), DR8‐Aβ(25–35), or Aβ(25–35).

Data information: Peptide concentration is 30 μM for each peptide. Standard deviations of the mean are shown as bars for each sample (N = 6 for pure peptide and N = 12 for mixture). The statistics were done by Student's t‐test.
Figure 3
Figure 3. Effect of intranasally delivered R8‐Aβ(25–35)‐PEI on APP/PS1 transgenic mice after 4‐month treatment
Wild‐type (WT) and APP/PS1 mice were treated with either PEI or R8‐Aβ(25–35)‐PEI from the age of 4 months to 8 months.
  1. A–C

    Morris water maze. (A) The plot of the escape latency. (B) The times of the indicated mice crossing the target quadrant. (C) Percentage of time the indicated mice spent swimming in the target quadrant where the hidden platform used to be. The behavior data were expressed in mean ± SEM. The statistics of the escape trend were done with two‐way ANOVA. Others were done by Student's t‐test.

  2. D, E

    ELISA of total Aβ40 and Aβ42 in hippocampus (D) and cortex (E) (N = 3 per group).

  3. F

    Level of IL‐6 and IL‐1β in the cortex (N = 3 per group).

Data information: The data were expressed in mean ± SD, and the statistics were done by Student's t‐test for panels (D–F).
Figure 4
Figure 4. Effect of intranasally delivered R8‐Aβ(25–35)‐PEI on APP/PS1 mice from 4 months to 13 months of age with a 1‐month break within this period
  1. A

    Representative MicroPET image of the transgenic mouse brains co‐registered with mouse T2‐weighted MRI brain template. CTX, cortex; HIP, hippocampus; AMY, amygdala.

  2. B

    Quantitation of [11C]PiB uptake in the cortex, hippocampus, amygdala, and olfactory bulb (N = 6 per group).

  3. C–F

    ELISA of SDS‐insoluble Aβ40 and Aβ42 in the cortex (C) and hippocampus (D) and SDS‐soluble Aβ40 and Aβ42 in the cortex (E) and hippocampus (F) (N = 5 per group).

Data information: Data were expressed in mean ± SD, and the statistics were conducted with the Student's t‐test.
Figure 5
Figure 5. Brain penetration of FITC‐(Ahx)‐CR 8‐Aβ(25–35)‐PEI after the third dosing via intranasal route
The mice were treated intranasally with FITC‐(Ahx)‐CR8‐Aβ(25–35)‐PEI (9 nmole/mouse/24 h) for three times. The mice were sacrificed, and their brains were perfused at 0.5, 2, 6, 12, and 24 h after the third treatment.

  1. Fluorescence spectra of the filtrates of mouse brain homogenates after passing through a 100‐kDa filter. The unbroken, dashed, and dotted lines represent three different mice.

  2. The amount of FITC‐(Ahx)‐CR8‐Aβ(25–35)‐PEI per brain at different times after the third peptide treatment. Data were expressed in mean ± SD (n = 3).

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