The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment
Abstract
:1. Introduction
2. Results
2.1. Assessment of Protein Accumulation Pathology in the APP/PS1 Transgenic Mouse Model of AD
2.1.1. Immunostaining Aβ Species, Synaptic Markers, and Lysosomal-Associated Membrane Protein 1 (LAMP1)
2.1.2. Colocalization of LAMP1 and the Aβ42 Degradation Product Aβ38 in Neurons
2.2. Positive CatB Modulation as a Compensatory Strategy in APP/PS1 Transgenic Mice
2.2.1. CatB Enhancement by Z-Phe-Ala-Diazomethylketone (PADK) is Associated with Improved Aβ42 Detoxification in Lysosomes
2.2.2. Positive CatB Modulator Reduces Protein Accumulation Events and Improves Synaptic and Cognitive Measures
2.3. Assessment of Positive CatB Modulation as a Potential Preventive Strategy in Models of Age-Related Cognitive Impairment
2.3.1. CatB Enhancement by PADK for Synaptic and Functional Improvements in Aged Female Fischer Rats
2.3.2. CatB Enhancement by PADK for Synaptic and Functional Improvements in Aged Mice
3. Discussion
4. Materials and Methods
4.1. Animal Models
4.2. Treatments
4.3. Behavioral Analyses
4.4. Sample Preparation for Analyses
4.5. Immunoblot Analysis
4.6. ELISA
4.7. Immunohistochemistry
4.8. Cathepsin B Activity and Proteasome Activity
4.9. Statistical Analysis
5. Patents
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
act Cat B | 30-kDa active cathepsin B |
Actb | β-actin gene |
AD | Alzheimer’s disease |
APP | amyloid precursor protein |
Cat B | cathepsin B |
CTF | carboxyl terminal fragment |
CPP | conditioned place preference |
DG | dentate gyrus |
H&E | hematoxylin and eosin |
iPSC | induced pluripotent stem cell |
LAMP1 | lysosomal-associated membrane protein 1 |
MCI | mild cognitive impairment |
mf | mossy fibers |
ml | molecular layer |
NCAM | neural cell adhesion molecule |
PADK | Z-Phe-Ala-diazomethylketone |
PCR | polymerase chain reaction |
PS1 | presenilin 1 |
qRT-PCR | real-time quantitative reverse transcription PCR |
SAB | spontaneous alternation behavior |
sg | stratum granulosum |
so | stratum oriens |
sp | stratum pyramidale |
veh | vehicle |
WT | wild type |
yg | young |
ZFA | Z-Phe-Ala-OH |
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Compound | Molecular Weight (g/mol) | CatB Change | GluR1 Recovery |
---|---|---|---|
PADK | 394.4 | 4.9-fold increase | 100% |
SD1002 | 446.5 | 3.1-fold increase | 100% |
BW1005 | 496.5 | 2.8-fold increase | 100% |
UP1A101 | 328.4 | 2.1-fold increase | 53% |
E64d | 342.4 | 1.7-fold increase | 39% |
Measurements | Results Determined after PADK Treatment |
---|---|
LAMP1-positive organelles/neuron | 97 ± 9% of vehicle-treated mice (N.S.) |
CatB-positive organelles/neuron | 98 ± 5% of vehicle-treated mice (N.S.) |
CatB mRNA in transgenic mice | −0.497 ΔΔCt compared to vehicle-treated mice (N.S.) |
CatB mRNA in Fischer rats | −0.599 ΔΔCt compared to vehicle-treated rats (N.S.) |
Proteasome activity | 117 ± 12% of vehicle-treated controls (N.S.) |
SRPX2 CatB-interacting protein | 95 ± 6% of vehicle-treated controls (N.S.) |
Body weight of 9-month female mice | 103.7 ± 1.9% of start weight (N.S.) |
Body weight of 9-month male mice | 104.9 ± 1.4% of start weight (N.S.) |
Body weight of 22-month male mice | 101.8 ± 0.6% of start weight (N.S.) |
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Hwang, J.; Estick, C.M.; Ikonne, U.S.; Butler, D.; Pait, M.C.; Elliott, L.H.; Ruiz, S.; Smith, K.; Rentschler, K.M.; Mundell, C.; et al. The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment. Int. J. Mol. Sci. 2019, 20, 4432. https://doi.org/10.3390/ijms20184432
Hwang J, Estick CM, Ikonne US, Butler D, Pait MC, Elliott LH, Ruiz S, Smith K, Rentschler KM, Mundell C, et al. The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment. International Journal of Molecular Sciences. 2019; 20(18):4432. https://doi.org/10.3390/ijms20184432
Chicago/Turabian StyleHwang, Jeannie, Candice M. Estick, Uzoma S. Ikonne, David Butler, Morgan C. Pait, Lyndsie H. Elliott, Sarah Ruiz, Kaitlan Smith, Katherine M. Rentschler, Cary Mundell, and et al. 2019. "The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment" International Journal of Molecular Sciences 20, no. 18: 4432. https://doi.org/10.3390/ijms20184432