Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy
Abstract
:1. Introduction
2. Major Established Pathological Features of AD
3. Increased Epileptiform Activity or Seizures in AD: An Emergent Common but Under-Recognized Feature
4. Increased EEG Abnormalities in AD Patients
5. Excitatory/Inhibitory (E/I) Imbalance Contributes to Altered Hyperexcitability and Cognitive Decline in AD
6. The Overlapping Mechanisms Identified in GE Associated with Mutations in GABRG2 and AD
7. Insights from GE into Understanding E/I Imbalance in AD
8. Insights from Ketogenic Diet Treatment in GE into Understanding E/I Imbalance and Seizure Occurrence in AD
9. Insights from GE into Understanding Impaired Cognition in AD
10. Endoplasmic Reticulum (ER) Stress Exists in Both GE and AD
11. ER Stress Leads to Impaired Membrane Protein Trafficking and Altered Synaptic Physiology
12. ER Stress, Proteostasis, and Reduced Membrane Protein Trafficking in AD
13. Increased ER Stress Can Cause Increased Neuroinflammation from Very Early on: Evidence from an Epilepsy Mouse Gabrg2+/Q390X
14. Impaired GABAergic Signaling Is a Converging Pathway of Pathophysiology in GE
15. Altered GABAergic Neurotransmission Including GABA Neurotransmitter, Receptors, and Transporters in AD
16. Impaired GABAergic Interneurons in AD
17. Altered GABA Level and Tonic Inhibition in AD
18. Treatment Opportunities for AD
19. Targeting GABAergic Neurotransmission as Treatment for AD
20. Targeting ER Stress as a Treatment Option in AD
21. Targeting Tau as a Treatment Option for AD and Insights from GE
22. Targeting Glutamatergic Neurotransmission as a Treatment Option for AD
23. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Mutation/Variants | Models | Postulated Mechanisms | Channel Function | Phenotypes | References |
---|---|---|---|---|---|---|
GABRG2 | Q390X | cells | Impaired oligomerization, ER retention | reduced | GEFS+, DS | [30] |
GABRG2 | R82Q | cells | Impaired oligomerization, ER Retention | reduced | FS, CAE | [117] |
GABRG2 | Q390X, W429X, W461X | cells | Impaired oligomerization, ER Retention | reduced | FS, GEFS+, DS | [77] |
GABRG2 | Q390X | mice | ER rentention, dominant negative suppression | reduced | [62] | |
GABRG2 | Q390X | Mice | protein accumulation, aggregation | reduced | GEFS+, DS | [118] |
GABRG2 | Q390X | mice | increased neuroinflamamtion | reduced | DS | [79] |
GABRG2 | IVS6+2T->G | cell mice | NMD, ERAD | reduced | CAE, FS | [119] |
GABRG2 | A106T, I107T, P282S, etc. | cell | ERAD, ER retention | reduced | DEE | [120] |
GABRG2 | S443delC | cells | ERAD, ER retention? | reduced | GEFS+ | [121] |
GABRB3 | N328D | cells | ERAD, ER retention | reduced | LGS | [74] |
GABRB3 | E357K | cells | ERAD, ER retention | reduced | JAE | [74] |
GABRA1 | A322D | cells | ERAD, ER retention | reduced | JME | [122] |
SLC6A1 | G234S | cells | ERAD, ER retention | reduced | DS | [51] |
SLC6A1 | P361T | cells | ERAD, ER retention | reduced | autism, CAE | [52] |
SLC6A1 | V125M | cells | ERAD, ER Retention | reduced | CAE, ADHD | [123] |
SLC6A1 | 22 mutations | cells | ER Retention, dominant negative effect? | reduced | various phenotypes | [53] |
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Kang, J.-Q. Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy. Int. J. Mol. Sci. 2021, 22, 7133. https://doi.org/10.3390/ijms22137133
Kang J-Q. Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy. International Journal of Molecular Sciences. 2021; 22(13):7133. https://doi.org/10.3390/ijms22137133
Chicago/Turabian StyleKang, Jing-Qiong. 2021. "Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy" International Journal of Molecular Sciences 22, no. 13: 7133. https://doi.org/10.3390/ijms22137133