Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer's disease

Daniela Marinho; Ildete Luísa Ferreira; Ricardo Lorenzoni; Sandra M Cardoso; Isabel Santana; A Cristina Rego

doi:10.1111/acel.13895

Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer's disease

Aging Cell. 2023 Aug;22(8):e13895. doi: 10.1111/acel.13895. Epub 2023 Jun 26.

Authors

Daniela Marinho^{1

2

3}, Ildete Luísa Ferreira^{1

2

3}, Ricardo Lorenzoni^{1

2

3}, Sandra M Cardoso^{1

3

4}, Isabel Santana^{1

3

4

5}, A Cristina Rego^{1

3

4}

Affiliations

¹ CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
² IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
³ CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
⁴ FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁵ Neurology Department, CHUC-Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Abstract

Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER-mitochondria cross-talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl-H3 in AD human cortex, and increased HDAC2-3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aβ_1-42 oligomers (AβO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER-Ca²⁺ retention and mitochondrial Ca²⁺ accumulation, mitochondrial depolarization and impaired ER-mitochondria cross-talk, as observed in 3xTg-AD mouse hippocampal neurons and AβO-exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial-associated ER membranes (MAM) in cells exposed to AβO upon Tac treatment, along with reduction in ER-mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER-mitochondria Ca²⁺ transfer and mitochondrial Ca²⁺ retention, while knockdown of HDAC3 decreased ER-Ca²⁺ accumulation in AβO-treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM-related proteins, and reduced Aβ levels. These data demonstrate that Tac normalizes Ca²⁺ signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac-mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER-mitochondria communication as a promising target for innovative therapeutics in AD.

Keywords: amyloid beta peptide; calcium; histone deacetylases; mitochondria; mitochondrial-associated ER membranes; tacedinaline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Endoplasmic Reticulum / metabolism
Histone Deacetylases / genetics
Humans
Mice
Mitochondria / metabolism

Substances

Amyloid beta-Peptides
Histone Deacetylases