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M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and

Claude-Henry Volmar^1,2, Hasib Salah-Uddin^3,2, Karolina J Janczura^3,2

¹Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136; CVolmar@med.miami.edu cwahlestedt@med.miami.edu.

Proceedings of the National Academy of Sciences of the United States of America

|October 27, 2017

Summary

A novel drug, M344, targets multiple Alzheimer's disease (AD) pathways by modulating gene expression. This histone deacetylase inhibitor significantly improved cognitive function in AD mice, offering a potential new therapeutic strategy.

Area of Science:

Neuroscience
Pharmacology
Epigenetics

Background:

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with insufficient therapeutic options.
Epigenetic dysregulation plays a crucial role in AD pathogenesis, affecting multiple gene and protein pathways.
A single-agent therapeutic approach targeting multiple AD-related pathways is needed.

Purpose of the Study:

To investigate the epigenetic effects of the small-molecule histone deacetylase inhibitor M344 on Alzheimer's disease (AD) related targets.
To evaluate the therapeutic potential of M344 in a triple transgenic mouse model of AD.

Main Methods:

Treatment of triple transgenic (APPsw/PS1M146V/TauP301L) mice with M344.
Assessment of gene expression changes related to amyloid-beta (Aβ) and tau pathology.
Evaluation of cognitive function using behavioral tests (Y-maze, novel object recognition, Barnes maze).

Main Results:

M344 reduced Aβ, tau phosphorylation, BACE, and APOEε4 gene expression.
M344 increased expression of beneficial AD-related genes including BDNF, ADAM10, and SIRT1.
M344 treatment significantly prevented cognitive decline in AD mice and demonstrated short brain exposure for potential pulsed dosing.

Conclusions:

The histone deacetylase inhibitor M344 effectively normalizes multiple pathogenic pathways implicated in Alzheimer's disease.
M344 demonstrates significant therapeutic potential by improving cognitive function in a relevant AD mouse model.
M344 exemplifies a multitargeting drug strategy for complex, polygenic diseases like Alzheimer's.

Keywords:

APP processing Alzheimer’s M344 epigenetics multitarget

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