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M₁ muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

ABSTRACT: Many dementias are propagated through the spread of "prion-like" misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer's disease (AD), for which no treatments are available to slow or stop progression. The M₁ acetylcholine muscarinic receptor (M₁ receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the M₁ receptor might slow the progression of neurodegeneration associated with prion-like misfolded protein in a mouse model of prion disease. Proteomic and transcriptomic analysis of the hippocampus revealed that this model had a molecular profile that was similar to that of human neurodegenerative diseases, including AD. Chronic enhancement of the activity of the M₁ receptor with the positive allosteric modulator (PAM) VU0486846 reduced the abundance of prion-induced molecular markers of neuroinflammation and mitochondrial dysregulation in the hippocampus and normalized the abundance of those associated with neurotransmission, including synaptic and postsynaptic signaling components. PAM treatment of prion-infected mice prolonged survival and maintained cognitive function. Thus, allosteric activation of M₁ receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.

SUBMITTER: Dwomoh L

PROVIDER: S-EPMC7616172 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

Dwomoh Louis L Rossi Mario M Scarpa Miriam M Khajehali Elham E Molloy Colin C Herzyk Pawel P Mistry Shailesh N SN Bottrill Andrew R AR Sexton Patrick M PM Christopoulos Arthur A Conn Jeffrey J Lindsley Craig W CW Bradley Sophie J SJ Tobin Andrew B AB

Science signaling 20221115 760

Many dementias are propagated through the spread of "prion-like" misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer's disease (AD), for which no treatments are available to slow or stop progression. The M1 acetylcholine muscarinic receptor (M1 receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the ...[more]

PMID: 36378750

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Project description:Purpose: evaluation of the neuroprotective effects of VU846 compound, a positive allosteric modulator highly specific for the M1 muscarinic receptor, using the Next-generation sequencing (NGS) technology in a context of neurodegeneration induced by prion disease. Methods: Tg37 hemizygous mice at 3 to 4 weeks were inoculated with either the Rocky Mountain Laboratory (RML) scrapie prion brain homogenate, causative of the neurodegeneration, or normal brain homogenate for control purposes. Mice were also daily injected with either the M1 specific positive allosteric modulator VU836 or vehicle. The drug treatment started at 7week post brain homogenate inoculations (wpi) and 11wpi. The hippocampi from 3 mice of each group (control + vehicle, control + VU846, prion + vehicle and prion + VU846) were subject to tot RNA extraction. Raw reads were then converted into Fastq format, mapped to the “mouse-mm10” genome using HISAT2 (Galaxy Version 2.1.0) and processed with the StringTie (Galaxy Version 1.3.3.2) for assembling and quantification. Differential gene expression comparisons were performed with DESeq2 statistical tool (Galaxy Version 2.11.40.2) and data further analysed with two online software suites, Gene Ontology Panther (http://www.pantherdb.org/) and Pathway Studio (www.pathwaystudio.com). Results: we use the bioinformatic tool Pathway Studio (www.pathwaystudio.com) to quantitatively assesses the changes in the transcriptome with gene functions reported in the literature to assign an actication score. Strikingly, up and down regulation of genes changed by prion disease promote neuroinflammation and Alzheimer’s disease (AD) (positive activation scores), whereas the M1R specific positive allosteric modulator VU846 treatment modified the expression of genes to inhibit the neuroinflammatory and neurodegenerative processes directly associated with AD (negative activation score). Among these are genes associated with the complement system, microglia and astrocyte activation. Furthermore, consistent with the notion that neuroinflammatory pathways were activated in prion disease and diminished by VU846, the GO Pathway analysis revealed enrichment of genes in pathways such as the complement cascade and chemokine/cytokine signalling. Conversely, a group of genes that were down-regulated in prion disease were transcribed at significantly higher levels in the prion-effect of animals treated with VU846. These genes were strongly associated with synaptic plasticity, learning and memory, cognition and synaptic transmission by the GO Pathway analysis. Conclusions: These data point to the possibility that specific features of neuroinflammation and disease-adaptation may be directly regulated by M1-receptor activity strongly reinforcing the concept that pharmaceutically targeting M1 muscarinic receptor is neuroprotective and it might lead to the development of new treatments of Alzheimer’s like neurodegenerative diseases.

Project description:Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrPSc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrPSc mediated neurodegeneration. While clearance of PrPSc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrPSc mediated neurodegeneration. Apoe-/- mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe-/- mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrPSc and dying neurons by microglia in Apoe-/- mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrPSc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.

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M₁ muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

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M<sub>1</sub> muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

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M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

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M&lt;sub&gt;1&lt;/sub&gt; muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

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OmicsDI is part of the ELIXIR infrastructure

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M₁ muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.

M<sub>1</sub> muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease.