APP Knock-In Mice Produce E22P-Aβ Exhibiting an Alzheimer’s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression
Abstract
:1. Introduction
2. Results
2.1. The Number of Toxic Conformers Increases with Age in the Brain of NL-P-F Mice
2.2. Aβ Plaques Accumulate in the Hippocampus and Cortex of NL-P-F Mice from Nine Months Onward, with Tau Hyperphosphorylation in the Hippocampus at Twelve Months
2.3. Cognitive Function Declines after 6 Months of Age in NL-P-F Mice
2.4. Synaptic Plasticity Is Reduced in the Hippocampal CA1 Region of NL-P-F Mice after Three Months
2.5. Glial Cell Activation Occurred for Three Months Even in the Absence of Aβ Deposition, and Gliosis Was Observed after Aβ Plaque Deposition
2.6. Dysregulation of Hypoxia-Inducible Factor (HIF) Expression in Hippocampal Tissue of NL-P-F Mice at Six Months of Age or Later
3. Discussion
3.1. The Production of Toxic Conformers Promotes Tau Hyperphosphorylation but Not Neuronal Loss
3.2. Toxic Conformers Cause Impairment of Synaptic Plasticity and Cognitive Function
3.3. Toxic Conformers Induce Neuroinflammation through Glial Cell Activation
3.4. Dysregulation of HIF-Related Molecules Contributes to the Progression of AD-Related Pathology in NL-P-F Mice
3.5. Limitation
4. Materials and Methods
4.1. Animals
4.2. Tissue Preparation
4.3. ELISA
4.4. Immunohistochemistry (IHC)
4.5. Behavioral Tests
4.6. Hippocampal Slice Preparation and Electrophysiological Recordings
4.7. Western Blot
4.8. Real-Time RT-PCR
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Primary Antibody | |||
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Product Name | Dilution Ratio | Supplier | Cat. No. |
Rabbit anti-Iba1 antibody | 1:1000 | Wako, Osaka, Japan | 019-19741 |
Mouse Anti-Human Amyloid β antibody (82E1) | 1:1000 | Immuno-Biological Laboratories, Gunma, Japan | 10323 |
Goat Anti-GFAP antibody | 1:1000 | Sigma, St. Louis, MO, USA. | SAB2500462 |
Mouse anti-NeuN antibody, clone A60 | 1:300 | EMD Millipore, Inc., Billerica, MA USA | MAB377 |
Mouse anti-PHF-1 antibody | 1:250 | Distributed by Dr. Peter Davies |
Secondary Antibody | |||
---|---|---|---|
Product Name | Dilution Ratio | Supplier | Cat. No. |
Alexa Fluor 488 donkey anti-mouse IgG (H+L) | 1:1000 | Molecular Probs, Inc., Eugene, OR, USA | A-21202 |
Alexa Fluor 594 donkey anti-rabbit IgG (H+L) | 1:1000 | Invitrogen, Inc., Carlsbad, CA, USA | A-21207 |
Alexa Fluor 405 donkey anti-goat IgG (H+L) | 1:1000 | Abcam PLC, Cambridge, UK | Ab175664 |
Gene Name | Forward Primer Reverse Primer | Length (bp) | Gene Bank Accession No. |
---|---|---|---|
GAPDH | 5′-CCAAGGTCATCCATGACAAC-3′ 5′-TTACTCCTTGGAGGCCATGT-3′ | 422 | AB017801 |
HIF-1α | 5′-AAGAAACCGCCTATGACGTG-3′ 5′-CCACCTCTTTTTGCAAGCAT-3′ | 301 | AF057308 |
HIF-1β | 5′-GCAGGATCAGAACACAGCAA-3′ 5′-CCTGGGTAAGGTTGGAGTGA-3′ | 301 | U61184 |
HIF-3α | 5′-AGAGAACGGAGTGGTGCTGT-3′ 5′-ATCAGCCGGAAGAGGACTTT-3′ | 301 | NM022528 |
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Maki, T.; Sawahata, M.; Akutsu, I.; Amaike, S.; Hiramatsu, G.; Uta, D.; Izuo, N.; Shimizu, T.; Irie, K.; Kume, T. APP Knock-In Mice Produce E22P-Aβ Exhibiting an Alzheimer’s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression. Int. J. Mol. Sci. 2022, 23, 13259. https://doi.org/10.3390/ijms232113259
Maki T, Sawahata M, Akutsu I, Amaike S, Hiramatsu G, Uta D, Izuo N, Shimizu T, Irie K, Kume T. APP Knock-In Mice Produce E22P-Aβ Exhibiting an Alzheimer’s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression. International Journal of Molecular Sciences. 2022; 23(21):13259. https://doi.org/10.3390/ijms232113259
Chicago/Turabian StyleMaki, Takahito, Masahito Sawahata, Ichiro Akutsu, Shohei Amaike, Genki Hiramatsu, Daisuke Uta, Naotaka Izuo, Takahiko Shimizu, Kazuhiro Irie, and Toshiaki Kume. 2022. "APP Knock-In Mice Produce E22P-Aβ Exhibiting an Alzheimer’s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression" International Journal of Molecular Sciences 23, no. 21: 13259. https://doi.org/10.3390/ijms232113259