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 language | English (US) |
|---|---|
| Pages (from-to) | 596-612 |
| Number of pages | 17 |
| Journal | Brain |
| Volume | 141 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2018 |
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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 journal › Article
}
TY - JOUR
T1 - K v 1.3 inhibition as a potential microglia-Targeted therapy for Alzheimer's disease
T2 - Preclinical proof of concept
AU - Maezawa, Izumi
AU - Nguyen, Hai M.
AU - Di Lucente, Jacopo
AU - Jenkins, David Paul
AU - Singh, Vikrant
AU - Hilt, Silvia
AU - Kim, Kyoungmi
AU - Rangaraju, Srikant
AU - Levey, Allan I.
AU - Wulff, Heike
AU - Jin, Lee-Way
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - amyloid-β
KW - microglia
KW - neuroinflammation
KW - potassium channel
UR - http://www.scopus.com/inward/record.url?scp=85041676575&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041676575&partnerID=8YFLogxK
U2 - 10.1093/brain/awx346
DO - 10.1093/brain/awx346
M3 - Article
C2 - 29272333
AN - SCOPUS:85041676575
VL - 141
SP - 596
EP - 612
JO - Brain
JF - Brain
SN - 0006-8950
IS - 2
ER -