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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 -
The Journal of Biological Chemistry Jun 2016γ-Secretase complexes achieve the production of amyloid peptides playing a key role in Alzheimer disease. These proteases have many substrates involved in important...
γ-Secretase complexes achieve the production of amyloid peptides playing a key role in Alzheimer disease. These proteases have many substrates involved in important physiological functions. They are composed of two constant subunits, nicastrin and PEN2, and two variable ones, presenilin (PS1 or PS2) and APH1 (APH1aL, APH1aS, or APH1b). Whether the composition of a given γ-secretase complex determines a specific cellular targeting remains unsolved. Here we combined a bidirectional inducible promoter and 2A peptide technology to generate constructs for the temporary, stoichiometric co-expression of six different combinations of the four γ-secretase subunits including EGFP-tagged nicastrin. These plasmids allow for the formation of functional γ-secretase complexes displaying specific activities and maturations. We show that PS1-containing γ-secretase complexes were targeted to the plasma membrane, whereas PS2-containing ones were addressed to the trans-Golgi network, to recycling endosomes, and, depending on the APH1-variant, to late endocytic compartments. Overall, these novel constructs unravel a presenilin-dependent subcellular targeting of γ-secretase complexes. These tools should prove useful to determine whether the cellular distribution of γ-secretase complexes contributes to substrate selectivity and to delineate regulations of their trafficking.
Topics: Amyloid Precursor Protein Secretases; Animals; Blotting, Western; COS Cells; Cell Membrane; Cells, Cultured; Chlorocebus aethiops; Endopeptidases; Endosomes; HEK293 Cells; Hippocampus; Humans; Membrane Proteins; Microscopy, Confocal; Neurons; Peptide Hydrolases; Presenilin-1; Presenilin-2; Protein Subunits; Protein Transport; Rats, Sprague-Dawley; trans-Golgi Network
PubMed: 27059953
DOI: 10.1074/jbc.M115.708297 -
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 -
Clinical Interventions in Aging 2016Alzheimer's disease (AD) is a progressive, neurodegenerative disease and the most common form of dementia in elderly people. It is an emerging public health problem that... (Review)
Review
Alzheimer's disease (AD) is a progressive, neurodegenerative disease and the most common form of dementia in elderly people. It is an emerging public health problem that poses a huge societal burden. Linkage analysis was the first milestone in unraveling the mutations in APP, PSEN1, and PSEN2 that cause early-onset AD, followed by the discovery of apolipoprotein E-ε4 allele as the only one genetic risk factor for late-onset AD. Genome-wide association studies have revolutionized genetic research and have identified over 20 genetic loci associated with late-onset AD. Recently, next-generation sequencing technologies have enabled the identification of rare disease variants, including unmasking small mutations with intermediate risk of AD in PLD3, TREM2, UNC5C, AKAP9, and ADAM10. This review provides an overview of the genetic basis of AD and the relationship between these risk genes and the neuropathologic features of AD. An understanding of genetic mechanisms underlying AD pathogenesis and the potentially implicated pathways will lead to the development of novel treatment for this devastating disease.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Apolipoprotein E4; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mutation; Presenilin-1; Presenilin-2; Risk Factors
PubMed: 27274215
DOI: 10.2147/CIA.S105769 -
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 -
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