Symposium
Brain network dysfunction in Alzheimer's disease: a new potential target for future therapy
シンポジウム
アルツハイマー病における脳回路失調:将来への臨床応用へ向けて |
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| 7月26日（金）15:13～15:43 第4会場（朱鷺メッセ 3F 301）
2S04a-1
New Approaches to Alzheimer’s: From Neural Deficits to Neural Stimulation
Annabelle C Singer（Singer Annabelle C）
Georgia Institute of Technology & Emory University
In this talk I will discuss deficits in neural activity in Alzheimer's disease (AD), the effects of driving neural activity on immune cells and immune signals in the brain, and new methods to drive rhythmic activity non-invasively. Spatial navigation deficits are one of the earliest symptoms of AD and the hippocampus is one of the areas first affected by the disease. First, I will describe how neural codes underlying memory-based spatial decisions fail in animal models Alzheimer's disease (AD). Using a virtual reality behavior paradigm to record and manipulate neural activity in transgenic mice, the primary animal model of AD, we found deficits in hippocampal neural activity early in the progression of the disease. We found deficits in synaptic efficacy during behavior and in patterns of activity that we have previously shown inform memory-guided decisions in spatial navigation. Next, I will discuss the effects of driving these patterns of activity that are lacking in AD model mice. I will describe new non-invasive methods we are developing to drive rhythmic neural activity non-invasively, especially gamma activity which we and others have shown is altered in AD, and the effects of this activity. We found that driving gamma non-invasively mobilized the immune system and reduced pathogenic proteins. Furthermore, driving gamma rapidly initiated a unique immune signaling cascade. These discoveries could lead to new therapies for Alzheimer's disease by driving specific patterns of neural activity to impact the disease at the cognitive, cellular, and molecular levels. | | 7月26日（金）15:43～16:13 第4会場（朱鷺メッセ 3F 301）
2S04a-2
Network abnormalities and interneuron dysfunction in Alzheimer disease
Jorge J Palop（Palop Jorge J）
University of California, San Francisco; Gladstone Institutes
Alzheimer disease (AD) results in deterioration of cognitive functions and abnormal patterns of neuronal network activity, but
the underlying mechanisms are poorly understood. The brain relies on oscillatory rhythmic activity, generated by inhibitory
interneurons, to organize information flow and precisely time the neuronal firing required for cognitive processing. We
discovered that impaired inhibitory parvalbumin (PV)‒expressing interneurons contribute to altered gamma oscillatory activity,
network hyperexcitability, and memory deficits in mouse model of AD. Inhibitory interneuron deficits in AD mouse models,
including J20 and APP/PS1 mice, are in part mediated by decreased levels of the interneuron‒predominant voltage‒gated
sodium channel Nav1.1 subunit. Importantly, restoring Nav1.1 levels by Nav1.1BAC overexpression enhanced interneuron‒
dependent gamma oscillatory activity and cognitive performance in J20 and APP/PS1 mice, revealing key functional roles for
Nav1.1‒ and PV cell‒dependent gamma oscillatory activity in cognition. We are now using genetically modified embryonic
interneuron precursors from the medial ganglionic eminence (MGE) as a source of inhibitory interneurons for modulating
interneuron function in mouse models of AD. Embryonic interneuron precursors retain a remarkable capacity for migration
and integration in adult host brains, where they fully mature into functional inhibitory interneurons. We discovered that
transplanting Nav1.1‒overexpressing, but not wildtype, MGE‒derived interneurons enhanced behavior‒related modulation of
gamma oscillatory activity, reduced network hypersynchrony, and improved cognitive function in AD mouse models. Overall,
these findings highlight the potential of Nav1.1 and inhibitory interneurons as a therapeutic target in AD and that disease‒
specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions. We will also discuss our translational efforts identifying small molecule Nav1.1 enhancers that increase Nav1.1 currents and
interneuron‒dependent gamma oscillations to develop novel therapies for conditions with impaired interneuron function,
including AD and Dravet syndrome. | | 7月26日（金）16:13～16:43 第4会場（朱鷺メッセ 3F 301）
2S04a-3
Identifying neurons in the brain most vulnerable to Alzheimer's disease
Abid Hussaini（Hussaini Abid）
Columbia University Medical Center
In Alzheimer's disease, misplacing objects, spatial disorientation and olfactory dysfunction are some of the earliest symptoms. The disease is characterized by the formation of amyloid beta plaques and tau neurofibrillary tangles, which first affects the entorhinal cortex and then spreads to other regions of the brain including the hippocampus. The neurons of entorhinal cortex and the hippocampus are involved in memory, which explains the early cognitive decline in Alzheimer's disease. We use mouse models of Alzheimer's disease that accumulate amyloid beta and tau pathology in a similar way as seen in humans. As expected, these mice are impaired in spatial memory, object recognition and odor discrimination tasks. Using in vivo electrophysiology, we have identified the neurons in the entorhinal cortex-hippocampal circuit that are most vulnerable to Alzheimer's disease pathology leading to neuronal dysfunction and altered network activity. We have found that amyloid beta causes neurons to become hyperactive while tau alone leads to neuronal hypoactivity. But in the mice that have both amyloid beta and tau in entorhinal cortex, hyperactivity caused by amyloid beta dominates the tau's effect on neurons. Finally, with the help of optogenetic and chemogenetic techniques, we have attempted to correct the neuronal activity to combat AD pathology and restore function. | | 7月26日（金）16:43～17:10 第4会場（朱鷺メッセ 3F 301）
2S04a-4
Impaired neural representation and gamma oscillations in the entorhinal-hippocampal circuit of knock-in Alzheimer model
Kei M Igarashi（五十嵐 啓）1,2
1カリフォルニア大学アーバイン校
2JST PRESTO
The entorhinal cortex has bidirectional connections with the hippocampus and plays a critical role in memory formation and retrieval. The entorhinal cortex is one of the most vulnerable regions in the brain in early stages of Alzheimer's disease (AD), a neurodegenerative disease with progressive memory impairments. Accumulating evidence from healthy behaving animals indicates that gamma oscillations (30 - 100 Hz) are critical for mediating interactions between EC and hippocampus. We recently reported that in vivo gamma oscillations in the EC are impaired in knock-in mouse model with mutated amyloid precursor protein (APP) (Nakazono et al., 2017). Cross-frequency coupling of gamma (30-100 Hz) oscillations to theta oscillations was reduced in the medial EC. Phase locking of spiking activity of layer II/III pyramidal cells to the gamma oscillations was significantly impaired. These data indicate that the neural circuit activities organized by gamma oscillations were disrupted in the medial entorhinal cortex of APP knock-in mice, and point to gamma oscillations as one of possible mechanisms underlying cognitive dysfunction in AD patients. I will update our recent findings and discuss how these results can be reconciled with findings by other presenters. | |
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