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

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 Aß1-42 oligomers (AßO) 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 AßO-exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial-associated ER membranes (MAM) in cells exposed to AßO 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 AßO-treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM-related proteins, and reduced Aß 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.

Modified Glutamatergic Postsynapse in Neurodegenerative Disorders.

The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses and specialized to allow for precise neuron-to-neuron transmission of information. The PSD is localized immediately underneath the postsynaptic membrane forming a major protein network that regulates postsynaptic signaling and synaptic plasticity. Glutamatergic synaptic dysfunction affecting PSD morphology and signaling events have been described in many neurodegenerative disorders, either sporadic or familial forms. Thus, in this review we describe the main protein players forming the PSD and their activity, as well as relevant modifications in key components of the postsynaptic architecture occurring in Huntington's, Parkinson's and Alzheimer's diseases.

Mitochondrial Ca2+ handling in Huntington's and Alzheimer's diseases - Role of ER-mitochondria crosstalk.

Mitochondria play a relevant role in Ca2+ buffering, governing energy metabolism and neuronal function. Huntington's disease (HD) and Alzheimer's disease (AD) are two neurodegenerative disorders that, although clinically distinct, share pathological features linked to selective brain damage. These include mitochondrial dysfunction, intracellular Ca2+ deregulation and mitochondrial Ca2+ handling deficits. Both diseases are associated with misfolding and aggregation of specific proteins that physically interact with mitochondria and interfere with endoplasmic reticulum (ER)/mitochondria-contact sites. Cumulating evidences indicate that impairment of mitochondrial Ca2+ homeostasis underlies the susceptibility to selective neuronal death observed in HD and AD; however data obtained with different models and experimental approaches are not always consistent. In this review, we explore the recent literature on deregulation of mitochondrial Ca2+ handling underlying the interplay between mitochondria and ER in HD and AD-associated neurodegeneration.

Aß and NMDAR activation cause mitochondrial dysfunction involving ER calcium release.

Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Aß) peptide. Aß interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Aß-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Aß, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aß + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Aß or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Aß or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Aß. Aß-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aß + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Aß + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Aß-mediated GluN2B-composed NMDARs activation.

FK506 ameliorates cell death features in Huntington's disease striatal cell models.

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by striatal neurodegeneration, involving apoptosis. FK506, an inhibitor of calcineurin (or protein phosphatase 3, formerly known as protein phosphatase 2B), has shown neuroprotective effects in several cellular and animal models of HD. In the present study, we show the protective effects of FK506 in two striatal HD models, primary rat striatal neurons treated with 3-nitropropionic acid (3-NP) and immortalized striatal STHdh cells derived from HD knock-in mice expressing normal (STHdh(7/7)) or full-length mutant huntingtin (FL-mHtt) with 111 glutamines (STHdh(111/111)), under basal conditions and after exposure to 3-NP or staurosporine (STS). In rat striatal neurons, FK506 abolished 3-NP-induced increase in caspase-3 activation, DNA fragmentation/condensation and necrosis. Nevertheless, in STHdh(111/111) cells under basal conditions, FK506 did not prevent, in a significant manner, the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, or alter Bax/Bcl-2 ratio, but significantly reverted caspase-3 activation. In STHdh(111/111) cells treated with 0.3mM 3-NP or 25 nM STS, linked to high necrosis, exposure to FK506 exerted no significant effects on caspase-3 activation. However, treatment of STHdh(111/111) cells exposed to 10nM STS with FK506 effectively prevented cell death by apoptosis and moderate necrosis. The results suggest that FK506 may be neuroprotective against apoptosis and necrosis under mild cell death stimulus in the presence of FLmHtt.