Journal Article

The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta

Chae, Sehyun, Kim, Hye Yun, Lee, Ha-Eun, Seo, Min-Duk, Jeong, Yoo Joo, Lin, Yuxi, Yang, Jerry, Kim, Jae-Ick, Lee, Hyun-ju, Lee, Young-Ho, Kim, Jieun, Leriche, Geoffray, Hoe, Hyang-Sook, Ehrlich, Rachel S., Lingl, Sascha Castro

2024

Overview

Background We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer’s disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. Methods To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. Results In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10 , a marker of AD-associated reactive astrocytes (RAs), and c1qa , a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10 , markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia ( cx3cr1 and p2ry12 ) and decreased the mRNA levels of a marker of proliferative region-associated microglia ( gpnmb ) and a marker of lipid-droplet-accumulating microglia ( cln3 ). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. Conclusions Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Alzheimer Disease - drug therapy / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Analysis / Animals / Biomedical and Life Sciences / Biomedicine / CA140 / Care and treatment / Cognition - drug effects / Diagnosis / Dopamine - metabolism / Dopamine D1 receptor / Dopamine receptors / Genetic aspects / Humans / Immunology / Learning and memory / LTP / Male / Mice / Mice, Inbred C57BL / Mice, Transgenic / Neurobiology / Neuroinflammatory Diseases - drug therapy / Neuroinflammatory Diseases - metabolism / Neurology / Neurosciences / Receptors, Dopamine D1 - metabolism / RNA sequencing / Signal Transduction - drug effects / Signal Transduction - physiology / Synapses - drug effects / Synapses - metabolism / Synapses - pathology / Tau