Premium
O5‐05‐06: EVALUATING TAU OLIGOMERS PASSIVE IMMUNOTHERAPY USING AGED TRANSGENIC ANIMALS OF TAUOPATHY
Author(s) -
Al-Lahham Rabab,
Bittar Alice,
Montalbano Mauro,
Carretero-Murillo Mariana,
McAllen Salome,
Bhatt Nemil,
Ellsworth Anna,
Kayed Rakez
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.3024
Subject(s) - tauopathy , genetically modified mouse , immunotherapy , tau pathology , monoclonal antibody , transgene , tau protein , neuroscience , antibody , biology , pathology , medicine , alzheimer's disease , immunology , disease , neurodegeneration , immune system , biochemistry , gene
California-Davis, Sacramento, CA, USA; University of California Davis, Davis, CA, USA. Contact e-mail: lwjin@ucdavis.edu Background:KCa3.1, an intermediate-conductance Ca-activated K channel, is expressed mainly in immune cells and constitutes a promising target for modulating microglia in brain disorders. We have investigated the in vivo significance of KCa3.1 in Alzheimer’s disease (AD). Methods:The functional expression of microglial KCa3.1 in the 5xFAD mouse model of AD and human AD brain tissue samples, compared with control brain samples, was studied using qPCR, immunohistochemistry, Western blotting, and whole-cell patch clamp techniques. A specific KCa3.1 inhibitor called Senicapoc was investigated for its pharmacokinetic (PK) properties and for its effects on rectifying AD-like deficits in Ab oligomer-activated hippocampal slices and 5xFAD mice. Results: Microglial KCa3.1 expression and channel activity were enhanced in the 5xFAD model and human AD brains. Ab oligomer-activated hippocampal slices showed enhanced microglial activation, neuronal damage, and impaired long-term potentiation (LTP), which were mitigated by pharmacological KCa3.1 blockade. The small molecule KCa3.1 blocker Senicapoc showed excellent PK properties including oral availability and brain penetrance. Longterm treatment of 5xFAD mice with Senicapoc reduced microglial activation, mitigated hippocampal LTP deficits, and reduced cerebral Ab load. Conclusions: Senicapoc was previously advanced to a Phase-3 clinical trial for sickle cell anemia and is a relatively safe drug. Our results provide a strong rationale to repurpose Senicapoc for the treatment of AD and/or mild cognitive impairment.