Lauren Dinh

Introduction. Alzheimer’s Disease (AD) is terminal neurodegenerative disorder that impacts 5 million people in the US and 44 million people worldwide. AD has a wide range of clinical presentations including retrograde amnesia, declarative memory loss, and difficulty with problem solving and language¹. The two predominant pathological hallmarks of AD are the development of neurofibrillary tangles (NFT) and beta-amyloid plaques which both impair synaptic transmission. The progression of neurofibrillary tangles promotes intracellular calcium dysregulation, while beta-amyloid plaques, which reduce postsynaptic glutamate receptors, are generated via disruption of the Wnt/Beta-catenin pathway^2,7,8. Currently, the primary therapeutic options are those pharmacological in nature, specifically cholinesterase inhibitors such as rivastigmine or NMDA inhibitors like memantine¹. Optogenetics is an emerging neuromodulatory technique that allows highly specific control for activation or deactivation of targeted neuronal populations. This indicates that it could be used as a therapeutic agent to specifically regulate pathways or cell-types involved in the pathogenesis of AD^4,8. Methods. Hippocampal microinjections of FKBP1b was given to male rats at either 13 months (long term memory) or 19 months (short term memory) of age. The rats then performed the Morris water maze test at 21 months old². Intracellular electrophysiological recordings were obtained from pyramidal-like cells. Immunohistochemical tests were also performed to detect FKBP1b expression in the medial entorhinal cortex³. In a separate set of experiments, transgenic mouse models of AD were treated intraperitoneally with different types of Wnt signaling inhibitors for 10 weeks. Following this, various behavioral tests such as the the Morris water maze test, novel object recognition tests, and open field tests were done⁷. Using a channelrhodpsinopsin made to produce long-lasting neuronal hyperexcitability, this was transduced into APP transgenic mice. Light stimulation of the brain and immunofluorescence of brain slices was done⁸. Results. FKBP1b can restore aging-related changes in gene expression in the hippocampus by negatively regulating intracellular calcium levels². MEC layer 3 pyramidal neurons develop aging-related calcium dysregulation at an earlier age than do CA1 neurons which mimics the progression of NFT production in early-stage AD³.The Wnt signaling pathway has the potential to trigger the pathogenesis of AD7. Optogenetic activation of hippocampal pathways involved in beta-amyloid pathology can augment its production⁸. Conclusion. Studies show that optogenetic stimulation of hippocampal pathways that contribute to the pathogenesis of AD can induce the production of pathological markers of the disease such as beta-amyloid.

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3. Gant JC, Kadish I, Chen K-C, et al. Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer’s Disease Neurofibrillary Tangles First Appear. Journal of Alzheimers Disease. 2018;66(4):1371-1378. doi:10.3233/jad-180618.
4. Kastanenka KV, Hou SS, Shakerdge N, et al. Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer’s Disease. Plos One. 2017;12(1). doi:10.1371/journal.pone.0170275.
5. Kyung T, Lee S, Kim JE, et al. Optogenetic control of endogenous Ca2 channels in vivo. Nature Biotechnology. 2015;33(10):1092-1096. doi:10.1038/nbt.3350.
6. Perusini JN, Cajigas SA, Cohensedgh O, et al. Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimers disease mice. Hippocampus. 2017;27(10):1110-1122. doi:10.1002/hipo.22756.
7. Tapia-Rojas C, Inestrosa NC. Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimers disease in J20-APP transgenic and wild-type mice. Journal of Neurochemistry. 2018;144(4):443-465. doi:10.1111/jnc.14278.
8. Yamamoto K, Tanei Z-I, Hashimoto T, et al. Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease. Cell Reports. 2015;11(6):859-865. doi:10.1016/j.celrep.2015.04.017.