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

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 Aβ1–42 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.

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

“…111 Additionally, while there is evidence of increased MAP kinase signaling in ALS patients as well as in animal and iPSC models, 57,[112][113][114][115] two compounds identified here were MAP kinase inhibitors (XMD-892, XMD-885). Finally, XMD-892 116 and other compounds (tacedinaline, [117][118][119] MLN4924, 120 piperlongumine, 121,122 prunetin 123 ) have also been under investigation for their antioxidant, anti-inflammatory, anti-ischemic, neuroprotective, and/or antitumour properties.…”

Uncovering the Early Events Associated with Oligomeric Aβ-Induced Src Activation

“…Primary hippocampal and cortical neurons from Tg2576 mice evidenced increased mitochondrial fission, decreased fusion and abnormal mitochondrial function [ 47 ]. Moreover, we previously demonstrated that prolonged AβO (1 μM, for up to 24 h) treatment caused mitochondrial fragmentation in mature primary hippocampal neurons [ 24 ] or in HT22 hippocampal cells without evidence of cell death [ 48 ]. Here, we evidence that short exposure to the same concentration of AβO is enough to induce a mild decrease in mitochondrial aspect ratio and an increase in mitochondrial circularity, supporting some degree of mitochondrial fragmentation.…”

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…The plasma cholesterol metabolite 27-hydroxycholesterol can induce an increase in HDAC activity, leading to aggravated synaptic damage in rats with Alzheimer’s disease (AD), resulting in impaired memory [ 103 ]. Moreover, HDAC also affects the crosstalk between endoplasmic reticulum-mitochondrial organelles in the hippocampus of AD mice and aggravates the microglial inflammatory response in the entorhinal cortex, causing cognitive impairment [ 104 , 105 ]. In addition, mice with conditional knockout of the HDAC9 gene from forebrain neurons reversed depressive disorders caused by chronic restraint stress [ 106 ].…”