Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice

Autor:	Yu Yang, Baochang Qi, Xu Wang, Rajesh Khanna, Weina Ju, Di Sun, Yingying Cheng
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine Male Pathology Morris water navigation task Apoptosis Hippocampus lcsh:RC346-429 Synapse 0302 clinical medicine Cognition APP/PS1 mice Cognitive decline Phosphorylation Receptor biology Intercellular Signaling Peptides and Proteins Collapsin response mediator protein family Alzheimer’s disease Genetically modified mouse medicine.medical_specialty Amyloid beta Genetic Vectors Mice Transgenic Nerve Tissue Proteins tau Proteins Adenoviridae Calcium channel-binding domain 3 03 medical and health sciences Cellular and Molecular Neuroscience Protein Domains Alzheimer Disease Memory mental disorders medicine Presenilin-1 Animals Humans Learning Molecular Biology Administration Intranasal lcsh:Neurology. Diseases of the nervous system Amyloid beta-Peptides business.industry Research Mice Inbred C57BL Disease Models Animal 030104 developmental biology HEK293 Cells biology.protein business Peptides 030217 neurology & neurosurgery
Zdroj:	Molecular Brain, Vol 13, Iss 1, Pp 1-11 (2020) Molecular Brain
ISSN:	1756-6606
Popis:	Calcium dysregulation is a key pathological event in Alzheimer’s disease (AD). In studying approaches to mitigate this calcium overload, we identified the collapsin response mediator protein 2 (CRMP2), an axonal guidance protein that participates in synapse dynamics by interacting with and regulating activity of N-methyl-D-aspartate receptors (NMDARs). We further identified a 15 amino acid peptide from CRMP2 (designated CBD3, for calcium-binding domain 3), that reduced NMDAR-mediated Ca2+ influx in cultured neurons and post-synaptic NMDAR-mediated currents in cortical slices. Whether targeting CRMP2 could be therapeutically beneficial in AD is unknown. Here, using CBD3, we tested the utility of this approach. Employing the APP/PS1 mouse model of AD which demonstrates robust pathophysiology including Aβ1–42 deposition, altered tau levels, and diminished cognitive functions, we asked if overexpression of CBD3 could rescue these events. CBD3 was engineered into an adeno-associated vector and nasally delivered into APP/PS1 mice and then biochemical (immunohistochemistry, immunoblotting), cellular (TUNEL apoptosis assays), and behavioral (Morris water maze test) assessments were performed. APP/PS1 mice administered adeno-associated virus (AAV, serotype 2) harboring CBD3 demonstrated: (i) reduced levels of Aβ1–42 and phosphorylated-tau (a marker of AD progression), (ii) reduced apoptosis in the hippocampus, and (iii) reduced cognitive decline compared with APP/PS1 mice or APP/PS1 administered a control virus. These results provide an instructive example of utilizing a peptide-based approach to unravel protein-protein interactions that are necessary for AD pathology and demonstrate the therapeutic potential of CRMP2 as a novel protein player in AD.
Databáze:	OpenAIRE
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