K v 1.3 inhibition as a potential microglia-Targeted therapy for Alzheimer's disease: Preclinical proof of concept

Izumi Maezawa, Hai M. Nguyen, Jacopo Di Lucente, David Paul Jenkins, Vikrant Singh, Silvia Hilt, Kyoungmi Kim, Srikant Rangaraju, Allan I. Levey, Heike Wulff, Lee-Way Jin

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-Targeted therapeutic approach is not yet available clinically. The potassium channels K v 1.3 and K ir 2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the ' M1-like pro-inflammatory' or ' M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-β oligomer-induced expression of K v 1.3 and K ir 2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed K v 1.3 and K ir 2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-β oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule K v 1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-β oligomer required K v 1.3 activity in vitro and in hippocampal slices. Since we further observed that K v 1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological K v 1.3 inhibition could mitigate the pathology induced by amyloid-β aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-β uptake by microglia. Collectively, these results provide proof-of-concept data to advance K v 1.3 blockers to Alzheimer's disease clinical trials.

Original languageEnglish (US)
Pages (from-to)596-612
Number of pages17
JournalBrain
Volume141
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Microglia
Amyloid
Alzheimer Disease
Therapeutics
Transgenic Mice
Pathology
Neuronal Plasticity
Inhibition (Psychology)
Potassium Channels
Brain
Anti-Inflammatory Agents
Clinical Trials
Pharmacology
In Vitro Techniques

Keywords

  • Alzheimer's disease
  • amyloid-β
  • microglia
  • neuroinflammation
  • potassium channel

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

K v 1.3 inhibition as a potential microglia-Targeted therapy for Alzheimer's disease : Preclinical proof of concept. / Maezawa, Izumi; Nguyen, Hai M.; Di Lucente, Jacopo; Jenkins, David Paul; Singh, Vikrant; Hilt, Silvia; Kim, Kyoungmi; Rangaraju, Srikant; Levey, Allan I.; Wulff, Heike; Jin, Lee-Way.

In: Brain, Vol. 141, No. 2, 01.02.2018, p. 596-612.

Research output: Contribution to journalArticle

Maezawa, Izumi ; Nguyen, Hai M. ; Di Lucente, Jacopo ; Jenkins, David Paul ; Singh, Vikrant ; Hilt, Silvia ; Kim, Kyoungmi ; Rangaraju, Srikant ; Levey, Allan I. ; Wulff, Heike ; Jin, Lee-Way. / K v 1.3 inhibition as a potential microglia-Targeted therapy for Alzheimer's disease : Preclinical proof of concept. In: Brain. 2018 ; Vol. 141, No. 2. pp. 596-612.
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