In:
Alzheimer's & Dementia, Wiley, Vol. 19, No. S1 ( 2023-06)
Abstract:
Biased G protein‐coupled receptor (GPCR) ligands preferentially activate G protein‐ or β‐arrestin signaling pathways and are leading to the development of drugs with superior efficacy and reduced side‐effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer’s disease (AD), biased GPCR signaling is an unexplored area of investigation in AD. Previous work demonstrated that Gpr3 deficiency ameliorates amyloid‐β (Aβ) pathology. However, Gpr3‐deficient mice display several adverse phenotypes, including elevated anxiety‐like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein‐signaling. We hypothesized that generation of a G protein‐biased GPR3 mouse model, which maintains G protein‐signaling while eliminating β‐arrestin signaling, would attenuate AD‐associated phenotypes while preserving the beneficial effects of GPR3‐mediated G protein‐signaling. Methods We used a CRISPR/Cas9 genome‐editing strategy to develop two novel G protein‐biased GPR3 mouse models. We utilized a broad range of molecular, cellular, and biochemical methodologies, including mass spectrometry, immunoblot and immunohistochemical analyses, RNA profiling, and behavioral testing to determine the physiological relevance of G protein‐biased GPR3 signaling in naïve mice and in the preclinical App NL‐G‐F AD mouse model. Results We determine that, in contrast to Gpr3‐deficient mice, G protein‐biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We then established that GPR3 is expressed in neurons, microglia, and astrocytes and is associated with cell‐type‐specific effects on AD pathogenesis. Accordingly, we determine that G protein‐biased signaling leads to a reduction in Aβ generation in neurons, the activation and hypertrophy of disease‐associated‐microglia (DAM) and pan‐reactive astrocytes, and to an increase in amyloid plaque compaction in App NL‐G‐F mice. Conclusions These studies provide the first demonstration of G protein‐biased signaling in neuronal regulation of Aβ generation and microglial and astrocytic regulation of neuroinflammation in a preclinical AD mouse model and open an exciting area of investigation on biased agonism as a therapeutic intervention strategy for AD.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2201940-6
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