Frequency-dependent exacerbation of Alzheimer\u2019s disease neuropathophysiology

Ksenia V Kastanenka,Shuko Takeda,Yee Fun Lee,Michal Arbel-Ornath,Heng Zhou,Danielle Feng,Jonathan M Hawkes,Amanda Lariviere,Stephen N Gomperts,Xiqun Chen,Brian J Bacskai,Alex Kim,Maria Calvo-Rodriguez,Robert Logan,Steven S Hou

doi:10.1038/s41598-019-44964-z

Ksenia V Kastanenka, Shuko Takeda + Show 13 more

Open Access

https://doi.org/10.1038/s41598-019-44964-z

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Abstract

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer’s disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of <1 Hz. The power, but not the frequency of slow oscillations is altered in a mouse model of AD. Optogenetic rescue of slow oscillations by increasing activity in cortical pyramidal neurons at the frequency of slow waves restores slow wave power, halts deposition of amyloid plaques and prevents neuronal calcium dysregulation. Here we determined whether driving this circuit at an increased rate would exacerbate the amyloid-dependent calcium dyshomeostasis in transgenic mice. Doubling the frequency of slow waves for one month with optogenetics resulted in increased amyloid beta - dependent disruptions in neuronal calcium homeostasis and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer’s disease pathology and should be considered an avenue for clinical treatment of AD patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity - dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.

Highlights

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer’s disease (AD)
Since optogenetic restoration of pyramidal cell activity that rescued slow oscillations halted the progression of AD pathophysiology, it was imperative to determine whether the frequency of optogenetic stimulation was a Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, 114 Sixteenth St., Charlestown, MA, 02129, USA
While restoration of physiological circuit dynamics is sufficient to attenuate the progression of Alzheimer’s disease pathology and should be considered when devising treatments for AD, pathophysiological stimulation of neuronal circuits leads to activity-dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction

Summary

Introduction

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer’s disease (AD). Optogenetic rescue of slow oscillations by increasing activity in cortical pyramidal neurons at the frequency of slow waves restores slow wave power, halts deposition of amyloid plaques and prevents neuronal calcium dysregulation. Restoring slow wave power at the normal frequency of 0.6 Hz by synchronizing cortical excitatory activity using light activation of Channelrhodopsin-2 (ChR2)-expressing pyramidal neurons stopped plaque deposition and prevented neuronal calcium elevations (calcium overload), characteristic of this animal model[2]. While restoration of physiological circuit dynamics is sufficient to attenuate the progression of Alzheimer’s disease pathology and should be considered when devising treatments for AD, pathophysiological stimulation of neuronal circuits leads to activity-dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction

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