Impaired Kv7 channel function in cerebral arteries of a tauopathy mouse model (rTg4510)

In tauopathies, such as Alzheimer's disease with or without concomitant amyloid β plaques, cerebral arteries display pathological remodeling, leading to reduced brain tissue oxygenation and cognitive impairment. The precise mechanisms that underlie this vascular dysfunction remain unclear. Kv7...

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Published in:	Physiological reports 2018-12, Vol.6 (23), p.e13920-n/a
Main Authors:	Jong, Inge E. M., Jepps, Thomas A.
Format:	Article
Language:	eng
Subjects:	Action Potentials Alzheimer's disease Alzheimers disease Amyloid Animals Cardiovascular Conditions, Disorders and Treatments Cerebral Arteries - metabolism Cerebral Arteries - physiopathology cerebral artery Cognitive ability Deactivation HEK293 Cells Humans KCNE KCNQ KCNQ Potassium Channels - genetics KCNQ Potassium Channels - metabolism Kv7 Channels Male Membrane Physiology Mice Neurodegenerative diseases Neurofibrillary tangles Neuroscience Original Research Oxygenation Plaques Potassium channels (voltage-gated) Potassium Channels, Voltage-Gated - metabolism rTg4510 Tau protein tauopathies Tauopathies - metabolism Transgenic mice
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Summary:	In tauopathies, such as Alzheimer's disease with or without concomitant amyloid β plaques, cerebral arteries display pathological remodeling, leading to reduced brain tissue oxygenation and cognitive impairment. The precise mechanisms that underlie this vascular dysfunction remain unclear. Kv7 voltage‐dependent K+ channels contribute to the development of myogenic tone in rat cerebral arteries. Thus, we hypothesized that Kv7 channel function would be impaired in the cerebral arteries of a tauopathy mouse model (rTg4510), which might underlie cerebral hypoperfusion associated with the development of neurofibrillary tangles in tauopathies. To test our hypothesis we performed wire myography and quantitative PCR on cerebral arteries, mesenteric arteries and the inferior frontotemporal region of the brain surrounding the middle cerebral artery from tau transgenic mice (rTg4510) and aged‐matched controls. We also performed whole‐cell patch clamp experiments on HEK293 cells stably expressing Kv7.4. Here, we show that Kv7 channels are functionally impaired in the cerebral arteries of rTg4510 mice, but not in mesenteric arteries from the same mice. The quantitative PCR analysis of the cerebral arteries found no change in the expression of the genes encoding the Kv7 channel α‐subunits, however, we found reduced expression of the ancillary subunit, KCNE5 (also termed KCNE1L), in the cerebral arteries of rTg4510 mice. In the brain, rTg4510 mice showed reduced expression of Kv7.3, Kv7.5, and Kv2.1. Co‐expression of KCNE5 with Kv7.4 in HEK293 cells produced larger currents at voltages >0 mV and increased the deactivation time for the Kv7.4 channel. Thus, our results demonstrate that Kv7 channel function is attenuated in the cerebral arteries of Tg4510 mice, which may result from decreased KCNE5 expression. Reduced Kv7 channel function might contribute to cerebral hypoperfusion in tauopathies, such as Alzheimer's disease. Cerebrovascular remodeling, leading to cerebral hypoperfusion, occurs in tauopathies such as Alzheimer's disease. This study implicates reduced Kv7 channel function in cerebral arteries from a tauopathy mouse model. The attenuation in Kv7 channel function may be caused by reduced expression of the ancillary subunit, KCNE5.
ISSN:	2051-817X