-
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 -
Journal of Alzheimer's Disease : JAD 2023Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is...
Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer's disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5' iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer's disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of "pseudo-hypoxia" being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Presenilin-1; Mutation; Iron
PubMed: 37718800
DOI: 10.3233/JAD-230313 -
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 -
Neurochemical Research Aug 2021Early-onset Alzheimer's disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized... (Review)
Review
Early-onset Alzheimer's disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.
Topics: Aging; Alzheimer Disease; Animals; Anticonvulsants; Comorbidity; Epilepsy; Humans; Mutation; Presenilin-1; Presenilin-2; Seizures
PubMed: 33929683
DOI: 10.1007/s11064-021-03332-y -
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 -
Current Protein & Peptide Science 2020Locating remedies for Alzheimer's disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of... (Review)
Review
Locating remedies for Alzheimer's disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of pathological events. This current lapse in AD diagnosis also limits the therapeutic efficiency of the drugs, which might have been effective if given at the earlier stages of the disease. The indicated situation directs towards the burgeoned need for an effective biomarker technique that will help in early detection of AD and would be imminently useful to facilitate improved diagnosis and stimulate therapeutic trials. Till date, the major biomarkers, specifically associated with AD detection, may help in determining the early-stage AD diagnosis and identifying alterations in the cellular proteome, offering deeper insight into disease etiology. Currently existing multidisciplinary clinical diagnosis of AD is a very tedious, expensive procedure and requires highly trained and skilled professionals who are rarely available outside the specialty clinics. Mutations in amyloid precursor protein (APP) or Presenilin 1 and 2 (PSEN1 and PSEN2) are some biomarkers acting as critical checkpoints for AD diagnosis. However, the presence of some associated biomarkers in cerebrospinal fluid (CSF) such as total-Tau (tTau), phosphorylated- Tau (pTau) 181 and Amyloid-β (Aβ) 1-42 using structural or functional imaging techniques is considered for confirmatory diagnosis of AD. Furthermore, the molecular diagnosis of AD incorporates various sophisticated techniques including immuno-sensing, machine learning, nano conjugation-based detections, etc. In the current review description, we have summarized the various diagnostic approaches and their relevance in mitigating the long-standing urgency of targeted diagnostic tools for detection of AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Biomarkers; Dementia; Diagnostic Tests, Routine; Gene Expression Regulation; Humans; Immunoassay; Neurogranin; Neurons; Phosphorylation; Presenilin-1; Presenilin-2; Proteomics; Signal Transduction; tau Proteins
PubMed: 32538723
DOI: 10.2174/1389203721666200615173213 -
International Journal of Molecular... Apr 2022Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD...
Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Humans; Melanoma; Presenilin-1; Wnt Signaling Pathway; beta Catenin
PubMed: 35563300
DOI: 10.3390/ijms23094904 -
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 -
Acta Neuropathologica Communications Sep 2021Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer's...
Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer's disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells. Interestingly, genetic inactivation of presenilin 1 (PS1) or both PS genes in mutant human Tau transgenic mice exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions (e.g., hippocampus, cortex and amygdala). Remarkably, neurofilament (NF) light chain (NF-L) and phosphorylated NF are abnormally accumulated in the brain of Tau mice lacking PS. Synchrotron infrared microspectroscopy revealed aggregated and oligomeric β-sheet structures in amyloid plaque-free PS-deficient Tau mice. Hippocampal-dependent memory deficits are associated with synaptic tau accumulation and reduction of pre- and post-synaptic proteins in Tau mice. Thus, partial loss of PS/γ-secretase in neurons results in temporal- and spatial-dependent tau aggregation associated with memory deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PSEN mutations.
Topics: Alzheimer Disease; Animals; Brain; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons; Phosphorylation; Presenilins; Protein Aggregation, Pathological; tau Proteins
PubMed: 34593029
DOI: 10.1186/s40478-021-01259-7