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1.
Int J Mol Sci ; 22(21)2021 Nov 04.
Article in English | MEDLINE | ID: mdl-34769380

ABSTRACT

Despite the well-accepted role of the two main neuropathological markers (ß-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.


Subject(s)
Alzheimer Disease/complications , Amyloid beta-Peptides/adverse effects , Cognition Disorders/pathology , Disease Models, Animal , Mitochondria/pathology , tau Proteins/metabolism , Amyloid beta-Protein Precursor/physiology , Animals , Cognition Disorders/etiology , Cognition Disorders/metabolism , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mitochondria/metabolism , Phosphorylation , Presenilin-1/physiology , Synapses , tau Proteins/genetics
2.
Prog Neurobiol ; 191: 101818, 2020 08.
Article in English | MEDLINE | ID: mdl-32380223

ABSTRACT

Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/therapy , Dendritic Spines , Genetic Therapy , Group IV Phospholipases A2/physiology , Group IV Phospholipases A2/therapeutic use , Hippocampus , Spatial Memory , Animals , Behavior, Animal/physiology , Disease Models, Animal , Female , Gene Expression Regulation/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic
3.
ACS Chem Neurosci ; 10(9): 4076-4101, 2019 09 18.
Article in English | MEDLINE | ID: mdl-31441641

ABSTRACT

Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Alzheimer Disease/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/metabolism , Acetylation , Histone Deacetylases/chemistry , Humans , Hydroxamic Acids/chemistry , Molecular Structure , Phosphoric Diester Hydrolases/metabolism , Structure-Activity Relationship
4.
Mol Ther Nucleic Acids ; 16: 26-37, 2019 Jun 07.
Article in English | MEDLINE | ID: mdl-30825670

ABSTRACT

A hexanucleotide GGGGCC expansion in intron 1 of chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The corresponding repeat-containing sense and antisense transcripts cause a gain of toxicity through the accumulation of RNA foci in the nucleus and deposition of dipeptide-repeat (DPR) proteins in the cytoplasm of the affected cells. We have previously reported on the potential of engineered artificial anti-C9orf72-targeting miRNAs (miC) targeting C9orf72 to reduce the gain of toxicity caused by the repeat-containing transcripts. In the current study, we tested the silencing efficacy of adeno-associated virus (AAV)5-miC in human-derived induced pluripotent stem cell (iPSC) neurons and in an ALS mouse model. We demonstrated that AAV5-miC transduces different types of neuronal cells and can reduce the accumulation of repeat-containing C9orf72 transcripts. Additionally, we demonstrated silencing of C9orf72 in both the nucleus and cytoplasm, which has an added value for the treatment of ALS and/or FTD patients. A proof of concept in an ALS mouse model demonstrated the significant reduction in repeat-containing C9orf72 transcripts and RNA foci after treatment. Taken together, these findings support the feasibility of a gene therapy for ALS and FTD based on the reduction in toxicity caused by the repeat-containing C9orf72 transcripts.

5.
ACS Chem Neurosci ; 10(3): 1765-1782, 2019 03 20.
Article in English | MEDLINE | ID: mdl-30525452

ABSTRACT

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).


Subject(s)
Alzheimer Disease/drug therapy , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Histone Deacetylase Inhibitors/pharmacology , Phosphodiesterase 5 Inhibitors/pharmacology , Acetylation/drug effects , Animals , Disease Models, Animal , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/drug effects , Histone Deacetylases/metabolism , Humans , Mice , Phosphodiesterase 5 Inhibitors/chemistry
6.
Eur J Med Chem ; 150: 506-524, 2018 Apr 25.
Article in English | MEDLINE | ID: mdl-29549837

ABSTRACT

We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.


Subject(s)
Alzheimer Disease/drug therapy , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Drug Design , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Phosphodiesterase 5 Inhibitors/pharmacology , Alzheimer Disease/metabolism , Cell Line , Dose-Response Relationship, Drug , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Structure , Neuroglia/drug effects , Phosphodiesterase 5 Inhibitors/chemical synthesis , Phosphodiesterase 5 Inhibitors/chemistry , Structure-Activity Relationship
7.
ACS Chem Neurosci ; 8(3): 638-661, 2017 03 15.
Article in English | MEDLINE | ID: mdl-27936591

ABSTRACT

A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.


Subject(s)
Alzheimer Disease/drug therapy , Histone Deacetylase Inhibitors/therapeutic use , Phosphodiesterase 5 Inhibitors/therapeutic use , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Adenosine Triphosphate/metabolism , Alzheimer Disease/pathology , Animals , Cell Line, Transformed , Cyclic GMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Humans , Leukocytes, Mononuclear , Mice , Microsomes, Liver/drug effects , Models, Molecular , Neuroglia/drug effects , Neurons/drug effects , Phosphodiesterase 5 Inhibitors/chemistry , Phosphodiesterase 5 Inhibitors/pharmacology
8.
J Med Chem ; 59(19): 8967-9004, 2016 10 13.
Article in English | MEDLINE | ID: mdl-27606546

ABSTRACT

Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).


Subject(s)
Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Phosphodiesterase 5 Inhibitors/chemistry , Phosphodiesterase 5 Inhibitors/pharmacology , Acetylation/drug effects , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Cell Line , Cells, Cultured , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Drug Design , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylases/metabolism , Humans , Mice , Models, Molecular , Phosphodiesterase 5 Inhibitors/chemical synthesis , Phosphodiesterase 5 Inhibitors/pharmacokinetics
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