P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice.
Mol Neurodegeneration. 2020-08-18; 15(1):
DOI: 10.1186/s13024-020-00396-2
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1. Mol Neurodegener. 2020 Aug 18;15(1):47. doi: 10.1186/s13024-020-00396-2.
P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau
transgenic mice.
Ruan Z(1), Delpech JC(1), Venkatesan Kalavai S(1), Van Enoo AA(1), Hu J(1), Ikezu
S(1), Ikezu T(2)(3)(4)(5).
Author information:
(1)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, 72 East Concord St, L-606B, Boston, MA, 02118, USA.
(2)Department of Pharmacology & Experimental Therapeutics, Boston University
School of Medicine, 72 East Concord St, L-606B, Boston, MA, 02118, USA.
.
(3)Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA,
02118, USA. .
(4)Center for Systems Neuroscience, Boston University, Boston, MA, 02118, USA.
.
(5)Neurology, Boston University School of Medicine, 72 East Concord St, L-606B,
Boston, MA, 02118, USA. .
BACKGROUND: Neuronal accumulation of misfolded microtubule-associated protein tau
is a hallmark of neuropathology in Alzheimer’s disease, frontotemporal dementia,
and other tauopathies, and has been a therapeutic target. Microglia can spread
tau pathology by secreting tau-containing exosomes, although the specific
molecular target is yet to be identified for the therapeutic intervention. P2X
purinoceptor 7 (P2RX7) is an ATP-gated cation channel, enriched in microglia and
triggers exosome secretion. The purpose of the study is to examine the
therapeutic effect of an orally applicable, CNS-penetrant P2RX7 specific
inhibitor on the early disease stage of a tauopathy mouse model.
METHODS: Three-months-old P301S tau mice were treated with P2RX7-specific
inhibitor GSK1482160 or vehicle for 30 days, followed by behavioral, biochemical
and immunohistochemical assessment. GSK1482160 was also tested for exosome
secretion from primary cultured murine astrocytes, neurons and microglia in
vitro.
RESULTS: Oral administration of GSK1482160 significantly reduced accumulation of
MC1+ and Alz50+ misfolded tau in hippocampal regions, which was accompanied with
reduced accumulation of Tsg101, an exosome marker, in hippocampal neurons.
Proximity ligation assay demonstrated complex formation of Alz50+ tau and Tsg101
in hippocampal neurons, which was reduced by GSK1482160. On the other hand,
GSK1482160 had no effect on microglial ramification or CD68 expression, which was
significantly enhanced in P301S mice, or pro/anti-inflammatory cytokine gene
expression. Strikingly, GSK1482160-treated P301S mice show significantly improved
working and contextual memory as determined by Y-maze and fear conditioning
tests. GSK1482160 also significantly increased accumulation of Tsg101 and CD81 in
microglia in vivo, suggesting its suppression of P2RX7-induced exosome secretion
from microglia. This effect was confirmed in vitro, as ATP-induced secretion of
tau-containing exosome was significantly suppressed by GSK1482160 treatment from
primary murine microglia, but not from neurons or astrocytes.
DISCUSSION: The oral administration of P2RX7 inhibition mitigates disease
phenotypes in P301S mice, likely by suppressing release of microglial exosomes.
P2RX7 could be a novel therapeutic target for the early stage tauopathy
development.
DOI: 10.1186/s13024-020-00396-2
PMCID: PMC7436984
PMID: 32811520