Chemokine Receptor Antagonists Prevent and Reverse Cofilin-Actin Rod Pathology and Protect Synapses in Cultured Rodent and Human iPSC-Derived Neurons

Synapse loss is the principal cause of cognitive decline in Alzheimer's disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, i...

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Published in:	Biomedicines Vol. 12; no. 1; p. 93
Main Authors:	Kuhn, Thomas B, Minamide, Laurie S, Tahtamouni, Lubna H, Alderfer, Sydney A, Walsh, Keifer P, Shaw, Alisa E, Yanouri, Omar, Haigler, Henry J, Ruff, Michael R, Bamburg, James R
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-01-2024
Subjects:	Actin Alzheimer's disease Amino acids amyloid-β Animal models Axonogenesis Chemokine receptors chemokine/cytokine receptor antagonists Chemokines cofilactin rods Cofilin Cognition & reasoning Cognitive ability CXCR4 protein Cytoskeleton Dementia Disease Excitotoxicity Filaments Glycoprotein gp120 Hippocampus human iPSC-derived neurons Methylation Monoclonal antibodies NAD(P)H oxidase Neurodegenerative diseases neurodegenerative proteinopathies Neurological diseases Neurons Pathology Peptide T Peptides Prion protein prion-dependent lipid rafts Proteins Reagents Rods β-Amyloid United States > US peptide-T prion-dependent lipid rafts cofilactin rods human iPSC-derived neurons chemokine/cytokine receptor antagonists amyloid-β HIV gp120 neurodegenerative proteinopathies DAPTA IL-6
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Summary:	Synapse loss is the principal cause of cognitive decline in Alzheimer's disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, intra-neurite bundles of cofilin-saturated actin filaments that can disrupt vesicular trafficking and cause synaptic loss. Rods are a brain pathology in human AD and mouse models of AD and ADRD. Eliminating rods is the focus of this paper. One pathway for rod formation is triggered in ~20% of rodent hippocampal neurons by disease-related factors (e.g., soluble oligomers of Amyloid-β (Aβ)) and requires cellular prion protein (PrP ), active NADPH oxidase (NOX), and cytokine/chemokine receptors (CCRs). FDA-approved antagonists of CXCR4 and CCR5 inhibit Aβ-induced rods in both rodent and human neurons with effective concentrations for 50% rod reduction (EC ) of 1-10 nM. Remarkably, two D-amino acid receptor-active peptides (RAP-103 and RAP-310) inhibit Aβ-induced rods with an EC of ~1 pM in mouse neurons and ~0.1 pM in human neurons. These peptides are analogs of D-Ala-Peptide T-Amide (DAPTA) and share a pentapeptide sequence (TTNYT) antagonistic to several CCR-dependent responses. RAP-103 does not inhibit neuritogenesis or outgrowth even at 1 µM, >10 -fold above its EC . N-terminal methylation, or D-Thr to D-Ser substitution, decreases the rod-inhibiting potency of RAP-103 by 10 -fold, suggesting high target specificity. Neither RAP peptide inhibits neuronal rod formation induced by excitotoxic glutamate, but both inhibit rods induced in human neurons by several PrP /NOX pathway activators (Aβ, HIV-gp120 protein, and IL-6). Significantly, RAP-103 completely protects against Aβ-induced loss of mature and developing synapses and, at 0.1 nM, reverses rods in both rodent and human neurons (T ~ 3 h) even in the continuous presence of Aβ. Thus, this orally available, brain-permeable peptide should be highly effective in reducing rod pathology in multifactorial neurological diseases with mixed proteinopathies acting through PrP /NOX.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2227-9059 2227-9059
DOI:	10.3390/biomedicines12010093