title: Intranasal Delivery of NEMO-Binding Domain Peptide Prevents Memory Loss in a Mouse Model of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is the most common form of dementia. Despite intense investigations, no effective therapy is available to halt its progression. We found that NF-κB was activated within the hippocampus and cortex of AD subjects and that activated forms of NF-κB negatively correlated with cognitive function monitored by Mini-Mental State Examination and global cognitive z score. Accordingly, NF-κB activation was also observed in the hippocampus of a transgenic (5XFAD) mouse model of AD. It has been shown that peptides corresponding to the NF-κB essential modifier (NEMO)-binding domain (NBD) of IκB kinase α (IKKα) or IκB kinase β (IKKβ) specifically inhibit the induction of NF-κB activation without inhibiting the basal NF-κB activity. Interestingly, after intranasal administration, wild-type NBD peptide entered into the hippocampus, reduced hippocampal activation of NF-κB, suppressed hippocampal microglial activation, lowered the burden of Aβ in the hippocampus, attenuated apoptosis of hippocampal neurons, protected plasticity-related molecules, and improved memory and learning in 5XFAD mice. Mutated NBD peptide had no such protective effect, indicating the specificity of our finding. These results suggest that selective targeting of NF-κB activation by intranasal administration of NBD peptide may be of therapeutic benefit for AD patients.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Rangasamy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Grant T
authors.initials: GT
authors.lastname: Corbett
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Avik
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Khushbu K
authors.initials: KK
authors.lastname: Modi
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.affiliation: Department of Microbiology and Immunology, Columbia University, New York, NY, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.|Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008822:Mice, Transgenic; D008875:Middle Aged; D018697:Nootropic Agents / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*
chemical_list: C467063:NBD peptide, mouse; D018697:Nootropic Agents; D010455:Peptides
keywords: Alzheimer’s disease; NBD peptide; NF-κB; memory; neuroinflammation; plasticity