Piezoelectric agonists to prevent or reverse abnormal amyloid deposition

An agonist, piezoelectric technology for pathological progression that addresses the lack of therapeutic strategies

Pending Publication Date: 2022-03-01
UNIVERSITY OF EASTERN FINLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Stroke, the third leading cause of death and disability in industrialized countries, also lacks effective treatment strategies

Method used

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  • Piezoelectric agonists to prevent or reverse abnormal amyloid deposition
  • Piezoelectric agonists to prevent or reverse abnormal amyloid deposition
  • Piezoelectric agonists to prevent or reverse abnormal amyloid deposition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Example 1. Piezo1 and Piezo2 are mechanosensory channels in microglial cell types

[0180] In the present invention, piezoelectric receptors were found in human induced pluripotent stem cell (hIPSC)-derived microglial cells. This clinically highly relevant model recapitulates microglial phenotypes at the developmental, functional, and transcriptome levels as well as the expression of microglial markers, giving us an unprecedented opportunity to study of microglial cells.

[0181] qRT-PCR data revealed the expression of mechanosensitive piezoelectric 1R in all types of microglia tested. To adequately quantify the presence of piezoelectric receptor expression levels, the inventors extended their data to mouse trigeminal neurons (mTG, Figure 1A , Figure 1B normalized for piezoelectric receptor expression in ), which is known to contain two types of receptors in mouse trigeminal neurons. The present inventors found that mouse astrocytes exhibited high levels of expres...

Embodiment 2

[0182] Example 2. Yoda-1 activates piezoelectric 1Ca in human microglial cells 2+ Influx and reverse Aβ effect

[0183] Following the first discovery of mechanosensation in microglia, use of Ca in hiPSC cells and the SV-40 cell line 2+Imaging tests the functional effects of Piezo1R in microglia. The hiPSC-derived microglia were selected by the expression levels of the piezoelectric 1R cell line to be closest to human postmortem microglia levels, and the SV-40 cell line was selected as the cell line with the highest expression level. In addition to mechanical stimulation, Piezo1R (but not Piezo2) channels can be coactivated by a small molecule called Yoda1. Taking advantage of this unique opportunity to activate the natural piezoelectric 1R mechanosensitive form, the inventors used 50 μM Yoda1 diluted in base solution, applying a fast solenoid valve-based perfusion system (Biologic 2000) that additionally generates small hydraulic. The results showed that although Piezo1R e...

Embodiment 3

[0187] Example 3. Activation of Yoda1 reduces the pro-inflammatory properties of microglia

[0188] Piezo activation and inhibition have functional consequences in microglia, as piezo-specific activation of Yoda1 significantly reduces LPS-induced pro-inflammatory activation (increased secretion of pro-inflammatory cytokines) in microglia, suggesting that Activation of piezoelectricity beneficially modulates microglial function ( Figure 2A ). Furthermore, Piezo activation by Yoda1 significantly protected iPSC-microglia from cytotoxicity ( Figure 2B )

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Abstract

The present invention relates to the diagnosis, prevention, delay or reversal of pathological progression associated with abnormal amyloid deposits, such as for example Alzheimer's disease (AD). More specifically, the methods comprise administering specific molecules acting as piezoelectric agonists, such as Yoda1, Jed1, Jed2 or functional analogs thereof, capable of modulating the activation of small glial cells to an anti-inflammatory state and / or interfering with the formation of amyloid-producing peptides and / or increasing their outflow from the central nervous system. These agonists are useful in disease states associated with or at risk of developing brain amyloidosis, such as Alzheimer's disease, Parkinson's disease, stroke, head trauma, brain amyloid angiopathy, spongioencephalopathy, and pruritus. All of the diseases are evidence of abnormal pro-inflammatory microglial cell activation.

Description

technical field [0001] The present invention relates to the diagnosis, prevention, delay or reversal of pathological progression associated with abnormal amyloid deposits, such as exemplified by Alzheimer's disease (AD). More specifically, the method involves administering specific molecules that act as piezoelectric agonists, such as Yoda1, Jedi1, Jedi2, or functional analogs thereof, capable of modulating the activation of microglia towards an anti-inflammatory state and / or interfering with Formation of amyloidogenic peptides and / or increase their egress from the central nervous system. These agonists are indicated for use in disease states associated with cerebral amyloidosis (such as Alzheimer's disease, Parkinson's disease, one or more head traumas, stroke, cerebral amyloid angiopathy, spongiform encephalopathy and pruritus), or are at risk of developing said disorders, all of which have evidence of abnormal pro-inflammatory microglial activation. [0002] technical bac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/497A61K31/341A61K31/381A61K45/06A61P25/28A61P25/00A61P25/16A61P9/00A61P17/04
CPCA61K31/497A61K31/341A61K31/381A61K45/06A61P25/28A61P25/00A61P25/16A61P9/00A61P17/04A61P9/10A61P29/00A61K31/164A61K31/232
Inventor T·马尔姆R·吉尼亚图林
Owner UNIVERSITY OF EASTERN FINLAND
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