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

Author:

Kuhn Thomas B.1,Minamide Laurie S.1,Tahtamouni Lubna H.12,Alderfer Sydney A.3,Walsh Keifer P.1ORCID,Shaw Alisa E.1,Yanouri Omar4,Haigler Henry J.5,Ruff Michael R.5ORCID,Bamburg James R.14ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA

2. Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa 13133, Jordan

3. Department of Chemical and Biological Engineering and School of Biomedical Engineering, Colorado State University, Fort Collins, CO 80523, USA

4. Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO 80523, USA

5. Creative Bio-Peptides, Inc., 10319 Glen Road, Suite 100, Potomac, MD 20854, USA

Abstract

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 (PrPC), 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 (EC50) of 1–10 nM. Remarkably, two D-amino acid receptor-active peptides (RAP-103 and RAP-310) inhibit Aβ-induced rods with an EC50 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, >106-fold above its EC50. N-terminal methylation, or D-Thr to D-Ser substitution, decreases the rod-inhibiting potency of RAP-103 by 103-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 PrPC/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 (T½ ~ 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 PrPC/NOX.

Funder

National Institutes of Aging, Neurological Disorders

Stroke and the NIH Office of the Director

Colorado State University Microscopy Imaging Core and generous donations to the CSU Development Fund

Publisher

MDPI AG

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