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

Claude Henry Volmar, Hasib Salah-Uddin, Karolina J. Janczura, Paul Halley, Guerline Lambert, Andrew Wodrich, Sivan Manoah, Nidhi H. Patel, Gregory Sartor, Neil Mehta, Nancy T.H. Miles, Sachi Desse, David Dorcius, Michael D. Cameron, Shaun P Brothers, Claes R Wahlestedt

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined ADrelated targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEϵ 4 gene expression. M344 increases the expression of ADrelevant genes: BDNF, α-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and ABCA7, among others. M344 increases sAPPα and CTFα APP metabolite production, both cleavage products of ADAM10, concordant with increased ADAM10 gene expression. M344 also increases levels of immature APP, supporting an effect on APP trafficking, concurrent with the observed increase in MINT2 and FE65, both shown to increase immature APP in the early secretory pathway. Chronic i.p. treatment of the triple transgenic (APPsw/PS1M146V/TauP301L)micewithM344, at doses as low as 3mg/kg, significantly prevented cognitive decline evaluated by Y-maze spontaneous alternation, novel object recognition, and Barnes maze spatial memory tests. M344 displays short brain exposure, indicating that brief pulses of daily drug treatment may be sufficient for longterm efficacy. Together, these data show that M344 normalizes several disparate pathogenic pathways related to AD. M344 therefore serves as an example of how a multitargeting compound could be used to address the polygenic nature of multifactorial diseases.

Original languageEnglish (US)
Pages (from-to)E9135-E9144
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number43
DOIs
StatePublished - Oct 24 2017

Fingerprint

Amyloid beta-Protein Precursor
Alzheimer Disease
Genes
Amyloid Precursor Protein Secretases
Gene Expression
Epigenomics
Histone Deacetylase Inhibitors
Secretory Pathway
Brain-Derived Neurotrophic Factor
vorinostat
Amyloid
Pharmaceutical Preparations
Phosphorylation
Brain
Proteins

Keywords

  • Alzheimer's
  • APP processing
  • Epigenetics
  • M344
  • Multitarget

ASJC Scopus subject areas

  • General

Cite this

M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory. / Volmar, Claude Henry; Salah-Uddin, Hasib; Janczura, Karolina J.; Halley, Paul; Lambert, Guerline; Wodrich, Andrew; Manoah, Sivan; Patel, Nidhi H.; Sartor, Gregory; Mehta, Neil; Miles, Nancy T.H.; Desse, Sachi; Dorcius, David; Cameron, Michael D.; Brothers, Shaun P; Wahlestedt, Claes R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 43, 24.10.2017, p. E9135-E9144.

Research output: Contribution to journalArticle

Volmar, CH, Salah-Uddin, H, Janczura, KJ, Halley, P, Lambert, G, Wodrich, A, Manoah, S, Patel, NH, Sartor, G, Mehta, N, Miles, NTH, Desse, S, Dorcius, D, Cameron, MD, Brothers, SP & Wahlestedt, CR 2017, 'M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 43, pp. E9135-E9144. https://doi.org/10.1073/pnas.1707544114
Volmar, Claude Henry ; Salah-Uddin, Hasib ; Janczura, Karolina J. ; Halley, Paul ; Lambert, Guerline ; Wodrich, Andrew ; Manoah, Sivan ; Patel, Nidhi H. ; Sartor, Gregory ; Mehta, Neil ; Miles, Nancy T.H. ; Desse, Sachi ; Dorcius, David ; Cameron, Michael D. ; Brothers, Shaun P ; Wahlestedt, Claes R. / M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 43. pp. E9135-E9144.
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abstract = "Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined ADrelated targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEϵ 4 gene expression. M344 increases the expression of ADrelevant genes: BDNF, α-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and ABCA7, among others. M344 increases sAPPα and CTFα APP metabolite production, both cleavage products of ADAM10, concordant with increased ADAM10 gene expression. M344 also increases levels of immature APP, supporting an effect on APP trafficking, concurrent with the observed increase in MINT2 and FE65, both shown to increase immature APP in the early secretory pathway. Chronic i.p. treatment of the triple transgenic (APPsw/PS1M146V/TauP301L)micewithM344, at doses as low as 3mg/kg, significantly prevented cognitive decline evaluated by Y-maze spontaneous alternation, novel object recognition, and Barnes maze spatial memory tests. M344 displays short brain exposure, indicating that brief pulses of daily drug treatment may be sufficient for longterm efficacy. Together, these data show that M344 normalizes several disparate pathogenic pathways related to AD. M344 therefore serves as an example of how a multitargeting compound could be used to address the polygenic nature of multifactorial diseases.",
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AU - Halley, Paul

AU - Lambert, Guerline

AU - Wodrich, Andrew

AU - Manoah, Sivan

AU - Patel, Nidhi H.

AU - Sartor, Gregory

AU - Mehta, Neil

AU - Miles, Nancy T.H.

AU - Desse, Sachi

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