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Alzheimer's Research & Therapy Jan 2024Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic...
Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases.
BACKGROUND
Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated.
METHODS
A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test.
RESULTS
Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice.
CONCLUSIONS
In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.
Topics: Mice; Animals; Alzheimer Disease; Histone Deacetylase Inhibitors; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Chromatography, Liquid; Aspartic Acid Endopeptidases; Tandem Mass Spectrometry; Mice, Transgenic; Cognitive Dysfunction; Disease Models, Animal; Amyloid beta-Protein Precursor; Presenilin-1; Hydroxamic Acids; Terphenyl Compounds
PubMed: 38245771
DOI: 10.1186/s13195-024-01384-0 -
Scientific Reports Aug 2023Familial Alzheimer's disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which...
Familial Alzheimer's disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which is the catalytic component of γ-secretase complex, are causal of FAD. Recently, the p.Ile416Thr (I416T) PSEN 1 mutation has been reported in large kindred in Colombia. However, cell and molecular information from I416T mutation is scarce. Here, we demonstrate that menstrual stromal cells (MenSCs)-derived planar (2D) PSEN 1 I416T cholinergic-like cells (ChLNS) and (3D) cerebral spheroids (CSs) reproduce the typical neuropathological markers of FAD in 4 post-transdifferentiating or 11 days of transdifferentiating, respectively. The models produce intracellular aggregation of APPβ fragments (at day 4 and 11) and phosphorylated protein TAU at residue Ser/Thr (at day 11) suggesting that iAPPβ fragments precede p-TAU. Mutant ChLNs and CSs displayed DJ-1 Cys-SO (sulfonic acid), failure of mitochondria membrane potential (ΔΨ), and activation of transcription factor c-JUN and p53, expression of pro-apoptotic protein PUMA, and activation of executer protein caspase 3 (CASP3), all markers of cell death by apoptosis. Moreover, we found that both mutant ChLNs and CSs produced high amounts of extracellular eAβ. The I416T ChLNs and CSs were irresponsive to acetylcholine induced Ca influx compared to WT. The I416T PSEN 1 mutation might work as dominant-negative PSEN1 mutation. These findings might help to understanding the recurring failures of clinical trials of anti-eAβ, and support the view that FAD is triggered by the accumulation of other intracellular AβPP metabolites, rather than eAβ42.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Presenilin-1; Neurons; Cholinergic Agents; Mutation
PubMed: 37553376
DOI: 10.1038/s41598-023-39630-4 -
Aging Cell Aug 2023Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates... (Observational Study)
Observational Study
Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
Topics: Humans; Male; Female; Adult; Brain; Positron-Emission Tomography; Magnetic Resonance Imaging; Presenilin-1; Mutation; Alzheimer Disease; Cognition; Amyloid beta-Peptides; tau Proteins; Longitudinal Studies; Cross-Sectional Studies; Biomarkers
PubMed: 37291760
DOI: 10.1111/acel.13871 -
Neural Regeneration Research Aug 2023Alzheimer's disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD,... (Review)
Review
Alzheimer's disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD. Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways. Tumor-derived and immortalized astrocytic cell lines, alongside the emerging technology of adult induced pluripotent stem cells, are widely used to study cellular dysfunction in AD. Surprisingly, no stable cell lines were available from genetic mouse AD models. Recently, we established immortalized hippocampal astroglial cell lines from amyloid-β precursor protein/presenilin-1/Tau triple-transgenic (3xTg)-AD mice (denominated as wild type (WT)- and 3Tg-iAstro cells) using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection, thereby maintaining natural heterogeneity of primary cultures. Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling, mitochondrial dysfunctions, disproteostasis, altered homeostatic and signaling support to neurons, and blood-brain barrier models. Here we provide a comparative overview of the most used models to study astrocytes in vitro, such as primary culture, tumor-derived cell lines, immortalized astroglial cell lines, and induced pluripotent stem cell-derived astrocytes. We conclude that immortalized WT- and 3Tg-iAstro cells provide a non-competitive but complementary, low-cost, easy-to-handle, and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.
PubMed: 36751778
DOI: 10.4103/1673-5374.363192 -
Neural Regeneration Research Dec 2023Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely...
Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely recognized therapeutic intervention for refractory epilepsy, has recently been proposed as a potential treatment for a variety of neurological diseases, including Alzheimer's disease. However, the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear. The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease. Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were randomly assigned to either a ketogenic diet or control diet group, and received their respective diets for a duration of 3 months. The findings show that ketogenic diet administration enhanced cognitive function, attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice, and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway. Collectively, these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation. This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.
PubMed: 37449643
DOI: 10.4103/1673-5374.373715 -
The FEBS Journal Dec 2023More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase-like (SPPL) proteases have been identified based on their... (Review)
Review
More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase-like (SPPL) proteases have been identified based on their sequence similarity to presenilins, a related family of intramembrane aspartyl proteases. Other than those for the presenilins, no high-resolution structures for the SPP/SPPL proteases are available. Despite this limitation, over the years bioinformatical and biochemical data have accumulated, which altogether have provided a picture of the overall structure and topology of these proteases, their localization in the cell, the process of substrate recognition, their cleavage mechanism, and their function. Recently, the artificial intelligence-based structure prediction tool AlphaFold has added high-confidence models of the expected fold of SPP/SPPL proteases. In this review, we summarize known structural aspects of the SPP/SPPL family as well as their substrates. Of particular interest are the emerging substrate recognition and catalytic mechanisms that might lead to the prediction and identification of more potential substrates and deeper insight into physiological and pathophysiological roles of proteolysis.
Topics: Peptide Hydrolases; Membrane Proteins; Artificial Intelligence; Aspartic Acid Endopeptidases; Presenilins
PubMed: 37786993
DOI: 10.1111/febs.16968 -
Cellular Signalling Apr 2024Calcium is a ubiquitous second messenger that is indispensable in regulating neurotransmission and memory formation. A precise intracellular calcium level is achieved...
Calcium is a ubiquitous second messenger that is indispensable in regulating neurotransmission and memory formation. A precise intracellular calcium level is achieved through the concerted action of calcium channels, and calcium exerts its effect by binding to an array of calcium-binding proteins, including calmodulin (CAM), calcium-calmodulin complex-dependent protein kinase-II (CAMK-II), calbindin (CAL), and calcineurin (CAN). Calbindin orchestrates a plethora of signaling events that regulate synaptic transmission and depolarizing signals. Vitamin D, an endogenous fat-soluble metabolite, is synthesized in the skin upon exposure to ultraviolet B radiation. It modulates calcium signaling by increasing the expression of the calcium-sensing receptor (CaSR), stimulating phospholipase C activity, and regulating the expression of calcium channels such as TRPV6. Vitamin D also modulates the activity of calcium-binding proteins, including CAM and calbindin, and increases their expression. Calbindin, a high-affinity calcium-binding protein, is involved in calcium buffering and transport in neurons. It has been shown to inhibit apoptosis and caspase-3 activity stimulated by presenilin 1 and 2 in AD. Whereas CAM, another calcium-binding protein, is implicated in regulating neurotransmitter release and memory formation by phosphorylating CAN, CAMK-II, and other calcium-regulated proteins. CAMK-II and CAN regulate actin-induced spine shape changes, which are further modulated by CAM. Low levels of both calbindin and vitamin D are attributed to the pathology of Alzheimer's disease. Further research on vitamin D via calbindin-CAMK-II signaling may provide newer insights, revealing novel therapeutic targets and strategies for treatment.
Topics: Humans; Vitamin D; Calcium Signaling; Calbindins; Calmodulin; Calcium; Alzheimer Disease; Calcium-Binding Proteins; Calcium Channels; Calcineurin; Calcium-Calmodulin-Dependent Protein Kinase Type 2
PubMed: 38211841
DOI: 10.1016/j.cellsig.2024.111043 -
BMC Neuroscience Dec 2023It has been suggested that exercise training and postbiotic supplement could decelerate the progress of functional and biochemical deterioration in double transgenic...
BACKGROUND
It has been suggested that exercise training and postbiotic supplement could decelerate the progress of functional and biochemical deterioration in double transgenic mice overexpresses mutated forms of the genes for human amyloid precursor protein (APP) and presenilin 1 (m146L) (APP/PS1). Our earlier published data indicated that the mice performed better than controls on the Morris Maze Test parallel with decreased occurrence of amyloid-β plaques in the hippocampus. We investigated the neuroprotective and therapeutic effects of high-intensity training and postbiotic supplementation.
METHODS
Thirty-two adult APP/PS1 mice were randomly divided into four groups: (1) control, (2) high-intensity training (3) postbiotic, (4) combined (training and postbiotic) treatment for 20 weeks. In this study, the whole hemibrain without hippocampus was used to find molecular traits explaining improved brain function. We applied qualitative RT-PCR for gene expression, Western blot for protein level, and Zymography for LONP1 activity. Disaggregation analysis of Aβ-40 was performed in the presence of Lactobacillus acidophilus and Bifidobacterium longum lysate.
RESULTS
We found that exercise training decreased Alzheimer's Disease (AD)-related gene expression (NF-kB) that was not affected by postbiotic treatment. The preparation used for postbiotic treatment is composed of tyndallized Bifidobacterium longum and Lactobacillus acidophilus. Both of the postbiotics effectively disaggregated amyloid-β/Aβ-40 aggregates by chelating Zn and Cu ions. The postbiotic treatment decreased endogenous human APP protein expression and mouse APP gene expression in the hemibrains. In addition, the postbiotic treatment elevated mitochondrial LONP1 activity as well.
CONCLUSION
Our findings revealed distinct mechanisms behind improved memory performance in the whole brain: while exercise training modulates NF-kB signaling pathway regulating immune response until postbiotic diminishes APP gene expression, disaggregates pre-existing amyloid-β plaques and activates mitochondrial protein quality control in the region of brain out of hippocampus. Using the above treatments complements and efficiently slows down the development of AD.
Topics: Mice; Male; Humans; Animals; Alzheimer Disease; Mice, Transgenic; NF-kappa B; Amyloid beta-Protein Precursor; Amyloid beta-Peptides; Brain; Hippocampus; Plaque, Amyloid; Disease Models, Animal; Presenilin-1; Mitochondrial Proteins; ATP-Dependent Proteases
PubMed: 38110905
DOI: 10.1186/s12868-023-00836-x -
The New England Journal of Medicine Jun 2024Variants in and (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive...
BACKGROUND
Variants in and (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the variant who also had two copies of the apolipoprotein E3 Christchurch variant ( ). Heterozygosity for the variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the variant is prevalent.
METHODS
We analyzed data from 27 participants with one copy of the variant among 1077 carriers of the variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the variant. Two participants underwent brain imaging, and autopsy was performed in four participants.
RESULTS
Among carriers of who were heterozygous for the variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of carriers without the variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the and variants who underwent brain imaging, F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent F-flortaucipir PET imaging, tau findings were limited as compared with persons with in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the and variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the variant but not the variant.
CONCLUSIONS
Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
Topics: Humans; Alzheimer Disease; Heterozygote; Presenilin-1; Female; Male; Middle Aged; Apolipoprotein E3; Age of Onset; Positron-Emission Tomography; Aged; Brain; Adult; Genes, Dominant; Colombia
PubMed: 38899694
DOI: 10.1056/NEJMoa2308583 -
Molecular Neurobiology Sep 2023Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity,...
Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity, and synaptic dysfunction can cause cognitive dysfunction and memory loss. Cholecystokinin (CCK) is one of the major neuropeptides in the brain, and plays a role as a neurotransmitter and growth factor. The level of CCK in the cerebrospinal fluid is decreased in AD patients. In this study, a novel CCK analogue was synthesized on the basis of preserving the minimum bioactive fragment of endogenous CCK to investigate whether the novel CCK analogue could improve synaptic plasticity in the hippocampus of the APP/PS1 transgenic mouse model of AD and its possible molecular biological mechanism. Our study found that the CCK analogue could effectively improve spatial learning and memory, enhance synaptic plasticity in the hippocampus, normalize synapse numbers and morphology and the levels of key synaptic proteins, up-regulate the PI3K/Akt signaling pathway and normalize PKA, CREB, BDNF and TrkB receptor levels in APP/PS1 mice. The amyloid plaque load in the brain was reduced by CCK, too. The use of a CCKB receptor antagonist and targeted knockdown of the CCKB receptor (CCKBR) attenuated the neuroprotective effect of the CCK analogue. These results demonstrate that the neuroprotective effect of CCK analogue is achieved by activating the PI3K/Akt as well as the PKA/CREB-BDNF/TrkB signaling pathway that leads to protection of synapses and cognition.
Topics: Mice; Animals; Alzheimer Disease; Neuroprotective Agents; Brain-Derived Neurotrophic Factor; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Neuronal Plasticity; Mice, Transgenic; Cognition; Hippocampus; Cholecystokinin; Signal Transduction; Disease Models, Animal; Amyloid beta-Protein Precursor; Amyloid beta-Peptides; Presenilin-1
PubMed: 37247071
DOI: 10.1007/s12035-023-03388-7