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Cell Reports Nov 2023During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of...
During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of Alzheimer's disease (AD), remarkable effort has been put into investigating molecular mechanisms behind this disease. Then, with the advent of 3D neuronal cultures and cerebral organoids (COs), several studies have demonstrated that this model can adequately mimic familial and sporadic AD. Therefore, we created an AD-CO model using iPSCs derived from patients with familial AD forms and explored early events and the progression of AD pathogenesis. Our study demonstrated that COs derived from three AD-iPSC lines with PSEN1(A246E) or PSEN2(N141I) mutations developed the AD-specific markers in vitro, yet they also uncover tissue patterning defects and altered development. These findings are complemented by single-cell sequencing data confirming this observation and uncovering that neurons in AD-COs likely differentiate prematurely.
Topics: Humans; Alzheimer Disease; Induced Pluripotent Stem Cells; Mutation; Neurons; Organoids; Presenilin-1; Presenilin-2
PubMed: 37864790
DOI: 10.1016/j.celrep.2023.113310 -
Journal of Alzheimer's Disease : JAD 2022The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in...
BACKGROUND
The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.
OBJECTIVE
Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences.
METHODS
A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting.
RESULTS
Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.
CONCLUSION
The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Pathology, Molecular; Presenilin-1; Sex Characteristics
PubMed: 34864660
DOI: 10.3233/JAD-210523 -
Biochemistry Jul 2019γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more...
γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more than 90 known substrates, the γ-secretase complex is considered "the proteasome of the membrane", with central roles in biology and medicine. The protease carries out hydrolysis within the lipid bilayer to cleave the transmembrane domain of the substrate multiple times before releasing secreted products. For many years, elucidation of γ-secretase structure and function largely relied on small-molecule probes and mutagenesis. Recently, however, advances in cryo-electron microscopy have led to the first detailed structures of the protease complex. Two new reports of structures of γ-secretase bound to membrane protein substrates provide great insight into the nature of substrate recognition and how Alzheimer's disease-causing mutations in presenilin might alter substrate binding and processing. These new structures offer a powerful platform for elucidating enzyme mechanisms, deciphering effects of disease-causing mutations, and advancing Alzheimer's disease drug discovery.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Cell Membrane; Cryoelectron Microscopy; Humans; Hydrolysis; Lipid Bilayers; Models, Molecular; Mutagenesis; Presenilin-1; Protein Conformation
PubMed: 31198028
DOI: 10.1021/acs.biochem.9b00401 -
International Journal of Molecular... May 2024Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the...
Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the pathogenesis of Alzheimer disease (AD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in the lysosomes of embryonic fibroblasts from Psen1-knockout (PS1-KO) and (PS2-KO) mice and was associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport in late endosomal/lysosomal compartments. Mass spectrometry and complementary biochemical analyses also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes and decreased NPC1, thereby resembling the changes in PS1-KO and PS2-KO cells. In turn, treatment of PS1-KO and PS2-KO mouse embryonic fibroblasts (MEFs) with the chaperone inducer arimoclomol partially normalized NPC1 expression and rescued lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by overexpression of NPC1. Collectively, these data indicate that a loss of PS function results in impaired protein N-glycosylation, which eventually causes decreased expression of NPC1 and intracellular cholesterol accumulation. This mechanism could contribute to the neurodegeneration observed in PS KO mice and potentially to the pathogenesis of AD.
Topics: Animals; Mice; Alzheimer Disease; Cholesterol; Fibroblasts; Glycosylation; Intracellular Signaling Peptides and Proteins; Lysosomes; Mice, Knockout; Neurons; Niemann-Pick C1 Protein; Presenilin-1; Presenilin-2
PubMed: 38791456
DOI: 10.3390/ijms25105417 -
Neuropharmacology Jun 2021Alzheimer's disease (AD) is an age-related neurodegenerative disease and characterized by dementia, memory decline, loss of learning and cognitive disorder. The main... (Review)
Review
Alzheimer's disease (AD) is an age-related neurodegenerative disease and characterized by dementia, memory decline, loss of learning and cognitive disorder. The main pathological features of AD are the deposition of amyloid plaques and the formation of neurofibrillary tangles (NFTs) in the brain. The current anti-AD drugs have shown unsatisfactory therapeutic results. Due to the complications and unclear pathogenesis, AD is still irreversible and incurable. Among several hypotheses proposed by the academic community, the amyloid cascade is widely recognized by scholars and supported by a large amount of evidences. However, controversy over pathogenic factors has also been ongoing. Increasing evidence has shown that amyloid-β (Aβ) and especially amyloid-β oligomers (AβOs) are highly neurotoxic and pathogenic agents that damage neurons, mediate various receptors in the downstream pathways, and ultimately lead to learning and cognitive dysfunction. However, efforts in developing inhibitors of Aβ or amyloid-β precursor protein (APP) have all failed to yield good clinical results. More recently, it has been demonstrated that sigma receptors, including sigma-1 and sigma-2 subtypes, may play critical roles in the regulation of binding and metabolism of AβOs in neuron cells and the pathophysiology of AD. Thus, sigma receptor ligands are being recognized as promising therapeutic agents for treating or ameliorating AD. This article will review the pathophysiology of AD and highlight the sigma ligands that display the capability of preventing or even reversing Aβ- and AβOs-induced neurotoxicity and blocking the signal transduction caused by AβOs.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Humans; Ligands; Neuroinflammatory Diseases; Neurons; Presenilins; Receptors, sigma; tau Proteins; Sigma-1 Receptor
PubMed: 33045243
DOI: 10.1016/j.neuropharm.2020.108342 -
Brain region-specific myelinogenesis is not directly linked to amyloid-β in APP/PS1 transgenic mice.Experimental Neurology Apr 2023Alzheimer's disease (AD) is characterized by aggregating amyloid beta-protein (Aβ). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related...
Alzheimer's disease (AD) is characterized by aggregating amyloid beta-protein (Aβ). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related functional deficits. However, it remains unclear whether Aβ, in either plaque or soluble form, could alter myelinogenesis in AD brains. By cell-lineage tracing and labeling, we found both myelinogenesis and Aβ deposits displayed a region-specific pattern in the 13-month-old APP/PS1 transgenic mouse brains. Aβ plaques cause focal demyelination, but only about 15% Aβ plaques are closely associated with newly formed myelin in the APP/PS1 brains. Further, the Aβ plaque total area and the amount of new myelin are not linearly correlated across different cortical regions, suggesting that Aβ plaques induce demyelination but may not exclusively trigger remyelination. To understand the role of soluble Aβ in regulating myelinogenesis, we chose to observe the visual system, wherein soluble Aβ is detectable but without the presence of Aβ plaques in the APP/PS1 retina, optic nerve, and optic tract. Interestingly, newly-formed myelin density was not significantly altered in the APP/PS1 optic nerves and optic tracts as compared to the wildtype controls, suggesting soluble Aβ probably does not change myelinogenesis. Further, treatment of purified oligodendrocyte precursor cells (OPCs) with soluble Aβ (oligomers) for 48 h did not change the cell densities of MBP positive cells and PDGFRα positive OPCs in vitro. Consistently, injection of soluble Aβ into the lateral ventricles did not alter myelinogenesis in the corpus callosum of NG2-CreErt; Tau-mGFP mice significantly. Together, these findings indicate that the region-dependent myelinogenesis in AD brains is not directly linked to Aβ, but rather probably a synergic result in adapting to AD pathology.
Topics: Mice; Animals; Amyloid beta-Peptides; Mice, Transgenic; Amyloid beta-Protein Precursor; Presenilin-1; Alzheimer Disease; Brain; Demyelinating Diseases; Disease Models, Animal; Plaque, Amyloid
PubMed: 36736651
DOI: 10.1016/j.expneurol.2023.114344 -
The International Journal of... Sep 2023Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we...
Rolipram Ameliorates Memory Deficits and Depression-Like Behavior in APP/PS1/tau Triple Transgenic Mice: Involvement of Neuroinflammation and Apoptosis via cAMP Signaling.
BACKGROUND
Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we explored whether PDE4 inhibitor rolipram might also improve the symptoms of comorbid AD and depression.
METHODS
APP/PS1/tau mice (10 months old) were treated with or without daily i.p. injections of rolipram for 10 days. The animal groups were compared in behavioral tests related to learning, memory, anxiety, and depression. Neurochemical measures were conducted to explore the underlying mechanism of rolipram.
RESULTS
Rolipram attenuated cognitive decline as well as anxiety- and depression-like behaviors. These benefits were attributed at least partly to the downregulation of amyloid-β, Amyloid precursor protein (APP), and Presenilin 1 (PS1); lower tau phosphorylation; greater neuronal survival; and normalized glial cell function following rolipram treatment. In addition, rolipram upregulated B-cell lymphoma-2 (Bcl-2) and downregulated Bcl-2-associated X protein (Bax) to reduce apoptosis; it also downregulated interleukin-1β, interleukin-6, and tumor necrosis factor-α to restrain neuroinflammation. Furthermore, rolipram increased cAMP, PKA, 26S proteasome, EPAC2, and phosphorylation of ERK1/2 while decreasing EPAC1.
CONCLUSIONS
Rolipram may mitigate cognitive deficits and depression-like behavior by reducing amyloid-β pathology, tau phosphorylation, neuroinflammation, and apoptosis. These effects may be mediated by stimulating cAMP/PKA/26S and cAMP/exchange protein directly activated by cAMP (EPAC)/ERK signaling pathways. This study suggests that PDE4 inhibitor rolipram can be an effective target for treatment of comorbid AD and depression.
Topics: Mice; Animals; Amyloid beta-Protein Precursor; Rolipram; Mice, Transgenic; Phosphodiesterase 4 Inhibitors; Neuroinflammatory Diseases; Presenilin-1; Depression; Alzheimer Disease; Amyloid beta-Peptides; Memory Disorders; Apoptosis; Disease Models, Animal
PubMed: 37490542
DOI: 10.1093/ijnp/pyad042 -
International Journal of Molecular... May 2021Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however,...
Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however, little is known about the expression of key genes involved in amyloid production by peripheral cells, such as lymphocytes, during the development of hypoxic-ischemic encephalopathy. We analyzed the gene expression of the , , and and by RT-PCR in the lymphocytes of post-asphyxia and control neonates. In all examined periods after asphyxia, decreased expression of the genes of the , and was noted in lymphocytes. Conversely, expression of and genes decreased on days 1-7 and 8-14 but increased after survival for more than 15 days. We believe that the expression of genes in lymphocytes could be a potential biomarker to determine the severity of the post-asphyxia neurodegeneration or to identify the underlying factors for brain neurodegeneration and get information about the time they occurred. This appears to be the first worldwide data on the role of the and genes associated with Alzheimer's disease in the dysregulation of neonatal lymphocytes after perinatal asphyxia.
Topics: Asphyxia; Case-Control Studies; Female; Gene Expression Regulation; Humans; Infant, Newborn; Lymphocytes; Male; Presenilin-1; Presenilin-2
PubMed: 34067945
DOI: 10.3390/ijms22105140 -
Alzheimer's & Dementia : the Journal of... Sep 2023Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred...
INTRODUCTION
Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.
METHODS
A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies.
RESULTS
13 variants had p<1×10 or p<1×10 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.
DISCUSSION
Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.
Topics: Humans; Clusterin; Colombia; Alzheimer Disease; Mutation; Amyloid; Presenilin-1; Age of Onset
PubMed: 36951251
DOI: 10.1002/alz.13021 -
British Journal of Pharmacology Oct 2022Notch1 activation mediated by γ-secretase is critical for angiogenesis. GeneCards database predicted that Caspase-4 (CASP4, with murine ortholog CASP11) interacts with...
BACKGROUND AND PURPOSE
Notch1 activation mediated by γ-secretase is critical for angiogenesis. GeneCards database predicted that Caspase-4 (CASP4, with murine ortholog CASP11) interacts with presenilin-1, the catalytic core of γ-secretase. Therefore, we investigated the role of CASP4/11 in angiogenesis.
EXPERIMENTAL APPROACH
In vivo, we studied the role of Casp11 in several angiogenesis mouse models using Casp11 wild-type and knockout mice. In vitro, we detected the effects of CASP4 on endothelial functions and Notch signalling by depleting or overexpressing CASP4 in human umbilical vein endothelial cells (HUVECs). The functional domain responsible for the binding of CASP4 and presenilin-1 was detected by mutagenesis and co-immunoprecipitation.
KEY RESULTS
Casp11 deficiency impaired adult angiogenesis in ischaemic hindlimbs, melanoma xenografts and Matrigel plugs, but not the developmental angiogenesis of retina. Bone marrow transplantation revealed that the pro-angiogenic effect depended on CASP11 derived from non-haematopoietic cells. CASP4 expression was induced by inflammatory factors and CASP4 knockdown decreased cell viability, proliferation, migration and tube formation in HUVECs. Mechanistically, CASP4/11 deficiency increased Notch1 activation in vivo and in vitro, while CASP4 overexpression repressed Notch1 signalling in HUVECs. Moreover, CASP4 knockdown increased γ-secretase activity. The γ-Secretase inhibitor DAPT restored the effects of CASP4 siRNA on Notch1 activation and angiogenesis in HUVECs. Notably, the catalytic activity of CASP4/11 was dispensable. CASP4 directly interacted with presenilin-1 through the caspase recruitment domain (CARD).
CONCLUSIONS AND IMPLICATIONS
These findings reveal a critical role of CASP4/11 in adult angiogenesis and make this molecule a promising therapeutic target for angiogenesis-related diseases in the future.
Topics: Amyloid Precursor Protein Secretases; Animals; Caspases; Caspases, Initiator; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Knockout; Neovascularization, Pathologic; Presenilin-1; RNA, Small Interfering; Receptor, Notch1; Receptors, Notch
PubMed: 35737588
DOI: 10.1111/bph.15904