Neuroprotective Effect of Optogenetics Varies With Distance From Channelrhodopsin-2 Expression in an Amyloid-β-Injected Mouse Model of Alzheimer’s Disease

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Optogenetics uses a combination of genetic engineering and light to activate or inhibit specific neurons in the brain. Objective: The objective of the study was to examine the effect of activation of glutamatergic neurons in the hippocampus of mice injected with Aβ1-42 on memory function and biomarkers of neuroinflammation and neuroprotection in the brain to elucidate the clinical utility of optogenetic neuromodulation in AD. Methods: AAV5–CaMKII–channelrhodopsin-2 (CHR2)–mCherry (Aβ-CHR2 mice) or AAV5—CaMKII–mCherry (Aβ-non-CHR2 mice) was injected into the dentate gyrus (DG) of the bilateral hippocampus of an Aβ1-42-injected mouse model of AD. The novel object recognition test was used to investigate working memory (M1), short-term memory (M2), and long-term memory (M3) after Aβ1-42 injection. Hippocampus tissues were collected for immunohistochemical analysis. Results: Compared to controls, M1 and M2 were significantly higher in Aβ-CHR2 mice, but there was no significant difference in M3; NeuN and synapsin expression were significantly increased in the DG of Aβ-CHR2 mice, but not in CA1, CA3, the subventricular zone (SVZ), or the entorhinal cortex (ENT); GluR2 and IL-10 expressions were significantly increased, and GFAP expression was significantly decreased, in CA1, CA3, the DG, and the SVZ of Aβ-CHR2 mice, but not in the ENT. Conclusion: Activation of glutamatergic neurons by optogenetics in the bilateral DG of an Aβ-injected mouse model of AD improved M1 and M2, but not M3. A single-target optogenetics strategy has spatial limitations; therefore, a multiple targeted optogenetics approach to AD therapy should be explored.

Optogenetics: implications for Alzheimer’s disease research and therapy

“…Robinson et al investigated the effect of optogenetic techniques on neurotransmitter signals and ascertained that optogenetically activating glutamatergic neurons could facilitate learning and memory by theta-wave generation in the hippocampus [ 158 ]. Optogenetic activation of glutamatergic neurons in the bilateral DG in AD has been shown to improve working and short-term but not long-term memory, associated with increased expression of glutamate receptors in the hippocampus [ 159 , 160 ]. It was also established that glutamate receptor upregulation varies in various hippocampus regions, suggesting that a single-target optogenetics strategy has spatial limitations and a multiple targeted optogenetics approach to AD therapy should be explored [ 160 ].…”

“…Optogenetic activation of glutamatergic neurons in the bilateral DG in AD has been shown to improve working and short-term but not long-term memory, associated with increased expression of glutamate receptors in the hippocampus [ 159 , 160 ]. It was also established that glutamate receptor upregulation varies in various hippocampus regions, suggesting that a single-target optogenetics strategy has spatial limitations and a multiple targeted optogenetics approach to AD therapy should be explored [ 160 ].…”

Optogenetic neuromodulation with gamma oscillation as a new strategy for Alzheimer disease: a narrative review

“…Optogenetic activation of glutamatergic neurons in Aβ-injected mice improves working memory and short-term memory without affecting long-term memory in the bilateral DG. This stimulation downregulates Aβ and upregulates neuronal nuclei, which are biomarkers of neuroprotection [10]. As antagonism of adenosine A 2A receptor (A 2A R) mimics memory impairment prevention in AD animal models [74][75][76][77], optogenetic activation of a chimeric rho-dopsin-adenosine A 2A R protein activates cyclic adenosine monophosphate (cAMP) signaling, which increases cAMP levels and mitogen-activated protein kinase phosphorylation.…”

“…Affluent diffuse Aβ plaques without neuritic dystrophy, microgliosis, astrocytosis, and tangle formation have been observed in people who died in their early to mid-teens because of familial AD [ 9 ]. Aβ42 oligomers, which have been isolated from late-onset AD brains, reduce synapse density, suppress prolonged potentiation, and reinforce prolonged synaptic depression in the rodent hippocampus [ 9 ], and intraventricular injection of Aβ42 oligomers damages memory in healthy mature rats [ 10 ].…”

Biophysical characterization of light-gated ion channels using planar automated patch clamp

“…So far, the most impactful optogenetic application has been manipulation of the electrical activity of neurons and cardiomyocytes using channelrhodopsins (ChRs), photoactivation of which results in passive transmembrane conductance. ChRs are widely used in neuroscience and cardiology research, and their potential to treat Alzheimer’s disease ( Cui et al, 2020 ), Parkinson’s disease ( Yu et al, 2020 ), epilepsy ( Paschen et al, 2020 ), cardiac arrythmias ( Cheng et al, 2020 ), and many other neurological, psychiatric and cardiological disorders has been demonstrated in animal models. A report of successful partial vision restoration in a blind human patient using a ChR was published last year ( Sahel et al, 2021 ).…”